- Email: [email protected]
CEA, CYFRA21-1 and SCC in non-small cell lung cancer
LUNG CANCER ELSEVIER
Lung Cancer 13 (1995) 169-176
CEA, CYFRA21-1 and SCC in non-small cell lung cancer D. Moro*a, D. Villemainb, J.P. Vuillezb, C. Agnius Delordb, C. Brambilla” ‘Department of Respiratory Medicine, Hopital A. Michallon BP21 7X, 38043 Grenoble cedex 9. France bDepartment of Nuclear medecine. LER VRA CNRS Hopital A. Michallon BP217X, 38043 Grenoble cedex 9. France
Received 27 January 1995; revision received 15 May 1995; accepted 22 May 1995
CEA, SCC and CYFRA 21-1weremeasuredin samplesof serumcoming from 105‘Non smallcell lung cancer’(NSCLC) patients.The presentstudy hasbeencarried out to compare thesemarkers,to analysetheir prognosticsignificanceand to determinethe bestcombination of tumor markers.The medianvalue and interquartile rangewere:CYFRA 21-1: 2,3 rig/ml, CEA: 3,7 @ml, SCC: 1,2 rig/ml. CEA demonstratedhigher values in adenocarcinomas (P= 0.04). SCC and CYFRA 21-1 were comparablein the different histologic groups. CYFRA 21-1 and CEA valueswere dependanton tumor stage.Advanced tumors (T3 and T4) demonstratedhigher serumCYFRA 21-1 level (P=O.O006). CYFRA 21-l washigher than 3,3 ngJmlin 36%of patients.CEA washigherthan 5 @ml in 38%of patientsand SCC washigherthan 2 @ml in 27%of patients.Patientswith a high CEA andCYFRAZI-1 serum levelhad a shortersurvival than thosewith a normalserumlevel. In a Cox regression analysis four variables( TNM stage,age,CYFRA 21-1and CEA level) werefound to be significant in the predictionof survival; CYFRA 21-1levelhad the lowestP value( P = 0.0002). The current study suggests the useof a combinationof CEA and CYFRA 21-1 in the clinical care of NSCLC. Keywor& Tumor markers;CEA; SCC; CYFRA21- 1; Lung cancer;Non-smallcell; Prognosis
l
Corresponding author.
0169-5002/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0169-5002(95)00485-J
170
D. More
er al. /Lung
Cancer
13 (1995)
169-176
1. Introdwtion
Lung cancer is the leading cause of cancer deaths in Europe. Non small cell lung cancers (NSCLC) account for approximately 80% of all lung cancer cases. At the time of diagnosis approximately 30% of patients with NSCLC are eligible for surgery and have the best chance of a curative treatment. The main prognostic factors at the onset of treatment are, the stage of disease and performance status. There is great need for a tumor marker for the follow up and therapy control of these tumors. Carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and very recently CYFRA 21-l have been proposed for NSCLC. Carcinoembryonic antigen seems moderately useful in lung cancer clinical management [l], SCC is elevated in squamous cell carcinomas but has a lower sensitivity than CEA [2] and CYFRA 211 has proved, in preliminary report [3,4] to be a valuable marker. The aims of the current study were to assess the usefulness of CEA, CYFRA 21-l and SCC in NSCLC, to analyse the prognostic significance of a high tumor marker level and to determine the best combination of tumor markers. 2. Materials
and methods
2.1. Patients The current study was done retrospectively using 10.5 samples of frozen serum stored at -70” in our serum bank. Blood was sampled from patients at the time of diagnosis from 1987 to 1991. All patients had pathologically confirmed NSCLC. Staging of NSCLC was established according to the TNM UICC 1988 stage grouping. Fifty three of these 105 patients underwent surgery and thus were classified according to the post operative pTNM staging [5]. Survival data were obtained from Hospital files, General Practitioners and death certificates from City Hall registries. 2.2. Methods CEA was measured with a solid phase sandwich type immunoradiometric assay (IRMA) using a monoclonal antibody coated tube and a polyclonal ‘251-labelled antibody as a tracer (RIA-gnost” CEA,Behringwerke AG, Marburg, Germany). SCC was assayed with a solid phase IRMA using monoclonal antibodies (Abbott Laboratories, USA). CYFRA21-1 was measured with a solid phase sandwich typeIRMA using monoclonal antibodies. (ELSA-CYFRA21-1, Cis Bio international, France). The detection limit was 0.2 rig/ml for CEA, 0.5 rig/ml for SCC and 0.05 rig/ml for CYFRA21-1. Based on a specificity level of 95% and following manufacturers instructions, the upper normal values were, respectively at 3.3 rig/ml for CYFRA 21-1, 5 rig/ml for CEA and 2 rig/ml for SCC. 2.3. Statistics The tumor markers were studied as a continuous value, comparing patients with the lowest value to those with the highest value. Non parametric analysis were used: differences between two independent groups were determined by means of the
D. More et al. /Lung Cancer 13 (1995) 169-176
111
Mann-Whitney U test, differences between more than two groups were determined by means of the Kruskal-Wallis one-way analysis of variance. The survival of patients with normal and abnormal values were also compared. Actuarial survival rates were calculated from the time of treatment until the first of January 1992, using the method of Kaplan and Meier. The statistical comparison of survival was performed using the two tailed log-rank test offered by the Statview 4.1 Survival Tool package (Abacus concept Inc, California). The relative importance of multiple prognostic factors on survival was estimated using the Cox’s proportional hazards regression model. This data analysis was also performed using the Statview 4.1 Survival Tool package. Eight variables (TNM stage, histology, Performance status WHO/ECOG, age, sex, CYFRA 21-1 CEA and SCC level) were studied. Scores were assigned to 5 of the 8 variables (TNM stage, histology, Performance status WHO/ECOG, age,sex). CYFRA 21-1, CEA and SCC level were studied as continuous variables. A P-value of less than 0.05 was considered statistically significant. 3. Results
One hundred and five patients were studied, among them were 22 adenocarcinemas, 11 large cell carcinomas and 72 epidermoid carcinomas as defined by the WHO classification [6]. There were 96 males and 9 females, the mean age of patients was 61 years (range 36-83). Fifty three patients underwent a surgical treatment. After surgery, pathological study showed, seven adenocarcinomas, four large cell carcinomas and 42 epidermoid carcinomas. Patients clinical stages are listed in Table 1. The median assay value and interquartile range, for CYFRA 21-1 were 2.3 rig/ml (0.9-5.7) in the 105 patients, for CEA 3.7 rig/ml (2.3-7.2) for SCC 1.2 @ml (0.7-2.5). In the current group of 105 patients the CYFRA 21-1 level was above 3.3 r&ml in about 36% of cases (Confidence interval at 95%: 25-45%), whereas CEA showed a true positive result in 38% of the cases (Confidence interval at 95%: 28-48%) and SCC in 27% of the cases (Confidence interval at 95%: 17-35%).
1 Histologic types of the 105 patients studied
Table
Histology
Adenocarcinema
Large cell carcinoma
Epidermoid carcinoma
Stage I Stage II Stage III Stage IV
7 0 8 7
3 0 4 4
38 I 21 12
172
D. More et al. /Lung Cancer 13 (1995) 169-176
Table 2 The median and interquartile range of CYFRAZI-1, diagnosis
CEA (@ml) CYFRAZI-1 (@ml) SCC (@ml)
CEA and SCC according to the histological
Adenocarcinoma
Large cell carcinoma
Epidermoid carcinoma
5.45 (2.8-7.7) 2.35 (0.9-3.7) 1.2 (0.5-2.2)
4.15 (3.1-28) 2.7 (0.9-17.3) 1 (0.5-2.1)
3.2 (2.1-6.1) 2.15 (0.9-5.7) 1.35 (0.8-3)
3.1. CYFRA 21-1, CEA, SCC and histologic type (Table 2)
The serum CYFRA 21-l level was comparable in the different histological groups (Kruskal Wallis test: P = 0.79, Mann Whitney U test between epidermoid carcinomas and adenocarcinomas + Large cell carcinomas: P = 0.87). Considering surgical patients, serum CEA level was significantfy higher in the adenocarcinoma group when compared with the other histological groups (Kruskal Wallis test: P = 0,04, Mann Whitney U test: P = 0,04). The serum SCC level was comparable in the different histological groups (Kruskal Wallis test: P = 0.73, Mann Whitney U test between epidermoid carcinomas and adenocarcinomas + Large cell carcinomas: P = 0.23).The percentage of positive results of CYFRA 21-l) CEA and SCC and their relation to histology are presented in Table 3. 3.2. CYFRA 21-1, CEA, SCC and tumor stage
The CYFRA 21-l values were clearly dependant on tumor stage. A significant difference in the CYFRA 21-l level was observed between the 4 TNM stages of disease in the 105 patients (Kruskal Wallis test: P = 0.001, Mann Whitney U test between stages I+11 and III+IV P = 0.0007). This difference was also noted in the pTNM of the 53 surgical patients (Kruskal Wallis test: P = 0.001, Mann Whitney U test between post operative stages I+11 and III P = 0.003) (Fig. 1). The CEA value were also dependant on tumor stage. A significant difference in the CEA level was observed between the 4 TNM stages of disease in the 105 patients (Kruskal Wallis test: P = 0.005, Mann Whitney U test between stages I+11 and III+IV P = 0.03). However there was no statistical difference in the CEA level between the 3 surgical stages (Kruskal Wallis test: P = 0.7, Mann Whitney U test between post operative
Table 3 Percentage of positive results in the epidermoid carcinomas and adenocarcinomas % of positive tests
CYFRA 21-l
CEA
xc
Epidermoid carcinomas Adenocarcinomas
36% 31%
31% 59%
30% 19%
173
D. More et al. /Lung Cancer 13 (1995) 169-176 10
-
7.5
-
Fig. 1. Median
and interquartile
range of CYFRA
21-l according
to surgical
TNM
stage.
stages I+11 and III P = 0.6). There was no statistical difference in the SCC level between the 4 clinical stages (Kruskal Wallis test: P = 0.32, Mann Whitney U test between post operative stages I+11 and III+IV P = 0,88), but when the surgical stages where considered, this difference reached significance (Kruskal Wallis test : P = 0.04, Mann Whitney U test between post operative stages I+11 and III P = 0.03) 3.3. CYFRA 21-1, CEA, SCC, tumor size and nodal stage in surgical patients
Patients who presented more advanced tumors (T3 and T4) demonstrated
pmtbability
of sumival
higher
%
100 80 60
0
I 250
0
I 750
I 500 tim
Fig. 2. Kaplan Meier test P = 0.003).
survival
curves of the 105 patients
I 1000
I 1250
( W-1 according
to the level of CYFRA
21-I (Log-Rank
174
D. More
el al. /Lung
Cancer
13 (1995)
Table 4 Multivariate survival analysis. results of the Cox’s proportional Variable Stage of disease I and II III and IV Histology Epidennoid Adenccarcinoma and large cell carcinoma PS (WHO/ECOG) 0 and 1 2 and 3 Age <60 860
Assigned Coefficient score 0.945
hazards regression model
Chi2
P-value
RXP coefficient
0.359
6.925
0.0085
2.572
-0.535
0.333
2.579
0.1083
0.586
-0.072
0.316
0.052
0.8194
0.930
-0.714
0.335
0.0332
0.490
0.9769
1.019
0.0002 0.0028 0.2987
1.042 1.004 0.961
0 1 0 I
0 I -2.130
0 1
SCX
Male
Standard error
169-176
0.019
0.653
0.041 0.003 -0.040
0.011 0.001 0.038
0.0008
0 I
CYFRA21-I level CEA level SCC level
13 688 8.928 1.080
serum CYFRAZl-1 level when compared with patients with smaller tumors (Mann Whitney U test between post operative Tl+T2 and T3+ T4 P = 0.0006, Kruskal Wallis test: between the 4 T groups P = 0.0006). The nodal involvement was classified into 3 groups NO to N2. Patients who presented mediastinal lymph node involvement (N2) had higher serum CY FRA2 1- 1 level when compared with patients with smaller tumors (NO and Nl) but the difference was not significant (Mann Whitney U test P = 0.0506, Kruskal Wallis test between the 3 N groups P = 0.27). There was no impact of tumor size nor nodal stage on the CEA level (Tumor size, Mann Whitney U test between post operative Tl +T2 and T3+ T4 P = 0.64, Kruskal Wallis test: between the 4 T groups P = 0.88, Nodal stage, Mann Whitney U test between post operative NO+Nl and N2 P = 0.2, Kruskal Wallis test: between the 3 N groups P = 0.23). XC level were dependant on tumor size (Mann Whitney U test between post operative Tl+T2 and T3+ T4 P = 0.0013, Kruskal Wallis test: between the 4 T groups P = 0.0078) but not on the nodal stage (Mann Whitney U test between post operative NO+Nl and N2 P = 0.73, Kruskal Wallis test: between the 3N groups P = 0.88) 3.4. Survival analysis
There was a significant
difference in survival between patients with a normal
D. More et al. /Lung Cancer 13 (1995) 169-176
175
CYFRAZl-1 level and those with an elevated level (Log-Rank test P = 0.003) (Fig. 2). Patients with a high CEA serum level proved as well to have a shorter survival than those with a normal serum level (Log-Rank test P = 0.041) whereas SCC showed no impact on survival (Log-Rank test P = 0.186). The variables used in the Cox regression analysis are shown in Table 4; the estimated prognostic value of each variable in relation to overall survival among the 105 patients studied is expressed as a P value. Four variables (TNM stage, age, CYFRA 21-1 and CEA level) were found to be significant in the prediction of survival; CYFRA 21-1 level had the lowest P value (P = 0,0002). Histology, Performance status WHO/ECOG, sex and SCC level were not significant predictors of survival (P> 0.1). 4. Discussion In the clinical care of ‘non-small cell lung cancer’ there is a great need of signiticant variables able to predict metastatic spread and prognosis. These variables are important for assigning therapy and for clinical trial design and reporting. A consensus has been reached on some clinical, biological and therapeutic prognostic factors in non-small cell lung cancer [7]. Tumor markers are biological variables mostly used in the follow up of cancer patients. There is no general agreement on their use as prognostic factors. In the current study we attempt to correlate the level of CEA,SCC and CYFRA 21-1 to the tumor burden and to evaluate their usefulness as prognostic variables. CEA was identified in 1965. This tumor marker is widely used during the follow up of various tumor i.e.: Colorectal cancers, Breast cancer. In the current study CEA demonstrated higher values in adenocarcinomas (P = 0,04). The CEA level was slightly correlated with the TNM stage however there was no impact of the T stage nor the N stage on this level. In previous reports summarised by Ferrigno [8], CEA level usually increase in advanced stages. In the present study and in the literature CEA level is a predictor of survival. Squamous cell carcinoma (SCC) antigen, first described in carcinomas of the uterine cervix was also elevated in squamous carcinomas of the bronchus and nasopharynx. In the current study, SCC levels were comparable in all histologic types. SCC level increased with the size of the tumor and the pTNM stage however no impact of the nodal stage was demonstrated. No prognostic impact has been found (P = 0.186). This last point is in contrast with several other studies which reported a possible prognostic value for SCC level [2,9]. CYFRA 2 l-1 assay measures Cytokeratin 19 fragment. This new marker has been proposed in non-small cell lung carcinomas. CYFRA21-1 has been widely investigated by Pujol [3]. CYFRA 21-1 has been shown to be elevated in Non small cell lung carcinomas and particularly squamous cell carcinomas. In our study no difference was observed between the different histologic groups. The percentage of positive results of CYFRA 21-1 was 36% in the current study. This percentage is quite inferior than what has been previously reported (52% [3], 40% [lo], 47% [4]). This number of positive tests is quite comparable with that of CEA and is clearly superior than that of SCC. In the current study, the CYFRA 21-1 values were dependant on clinical and sur-
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et al. /Lung
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169-176
gical tumor stages. The CYFRA 21-1 level increased with the tumor size (P = 0.0006) and the nodal stage. Although this last difference was not statistically significant in the current study, Pujol [3] has clearly demonstrated in a larger series, an impact of N stage on CYFRA21-1 level. Our study and others [3,1 l] showed in uni and multivariate analysis a correlation between CYFRA21-1 level and survival time, therefore CYFRAZl-1 seems to have a real prognostic value. The sensitivity of CYFRA21-1, CEA and SCC is low, these markers should not be used for the diagnosis of lung cancer, however when their level is increased at the time of diagnosis, they seem useful1 in the follow up of patients. Despite its dependence on tumor size SCC lacks of prognostic impact, is not dependant on TNM stage and is above the upper normal values in less than 30% of cases. From these data it seems that SCC has no clear clinical usefulness in ‘non-small cell lung cancers’. In contrast, both CYFRA21-1 and CEA are correlated with the tumor burden and are independant prognostic variables in the current population of patients. Therefore, these results may suggest to assay these two tumor markers in the work up of ‘non-small cell lung cancers’. However, prospectives studies are needed to establish the cost effectiveness of the combination of CEA and CYFRA21-1. Acknowledgements
Financial support was from INSERM, le Cancer.
Credits PHRC93,
Ligue Nationale
Contre
References [I J NIH. Carcinoembryonic antigen:its role as a marker in the management of cancer. Br Med J 1981; 282: 373-37s. (21 Body JJ, Sculier JP, Raymakers N et al. Evaluation of squamous carcinoma antigen as a new marker for lung cancer. Cancer 1990; 65: 1552-1556. [3] Pujol JL, Grenier J, Daures JP et al. Serum Fragment of Cytokeratin Subunit-19 measured by CYFRA31-I Immunoradiometric Assay as a Marker of Lung Cancer. Cancer Res 1993; 53: 61-66. [S] Stieber P, Hasholzner U, Boddenmiiller H, et al. CYFRA 21-1 A new marker in lung cancer. Cancer 1993; 72: 707-713. [5] Mountain CF. A new international staging system for lung cancer. Chest 1986; 89: 225-233. [6] The World Health Organisation. Histological typing of lung tumors: Second edition. Am J Clin Pathol 1982; 77: 123-136. [7] Feld R, Borges M, Giner V et al. Prognostic factors in non-small cell lung cancer. Lung Cancer 1994; II: S19-S23. [8] Ferrigno D, Buccheri G, Biggi A. Serum tumour markers in lung cancer: History, biology and clinical applications. Eur Respir J 1994, 7: 186-197. [9] Mizushima Y, Hirata H, Izumi S et al. Clinical significance of the number of positive tumor markers in assisting the diagnosis of lung cancer with multiple tumor marker assay. Oncology 1990; 47: 43-48. [IO] Van der gaast A, Schoenmakers CHH, Kok TC et al. Evaluation of a new tumour marker in patients with non-small-cell lung cancer: Cyfra21-I. Br J Cancer 1994; 69: 525-528. [I I] Niblinski J, Furman M, Chyczewska E et al. Evaluation of CYFRAZI-I as a new marker for non small cell lung cancer. Eur J Can Prev 1994; 3: 227-230.
Lung Cancer 13 (1995) 169-176
CEA, CYFRA21-1 and SCC in non-small cell lung cancer D. Moro*a, D. Villemainb, J.P. Vuillezb, C. Agnius Delordb, C. Brambilla” ‘Department of Respiratory Medicine, Hopital A. Michallon BP21 7X, 38043 Grenoble cedex 9. France bDepartment of Nuclear medecine. LER VRA CNRS Hopital A. Michallon BP217X, 38043 Grenoble cedex 9. France
Received 27 January 1995; revision received 15 May 1995; accepted 22 May 1995
CEA, SCC and CYFRA 21-1weremeasuredin samplesof serumcoming from 105‘Non smallcell lung cancer’(NSCLC) patients.The presentstudy hasbeencarried out to compare thesemarkers,to analysetheir prognosticsignificanceand to determinethe bestcombination of tumor markers.The medianvalue and interquartile rangewere:CYFRA 21-1: 2,3 rig/ml, CEA: 3,7 @ml, SCC: 1,2 rig/ml. CEA demonstratedhigher values in adenocarcinomas (P= 0.04). SCC and CYFRA 21-1 were comparablein the different histologic groups. CYFRA 21-1 and CEA valueswere dependanton tumor stage.Advanced tumors (T3 and T4) demonstratedhigher serumCYFRA 21-1 level (P=O.O006). CYFRA 21-l washigher than 3,3 ngJmlin 36%of patients.CEA washigherthan 5 @ml in 38%of patientsand SCC washigherthan 2 @ml in 27%of patients.Patientswith a high CEA andCYFRAZI-1 serum levelhad a shortersurvival than thosewith a normalserumlevel. In a Cox regression analysis four variables( TNM stage,age,CYFRA 21-1and CEA level) werefound to be significant in the predictionof survival; CYFRA 21-1levelhad the lowestP value( P = 0.0002). The current study suggests the useof a combinationof CEA and CYFRA 21-1 in the clinical care of NSCLC. Keywor& Tumor markers;CEA; SCC; CYFRA21- 1; Lung cancer;Non-smallcell; Prognosis
l
Corresponding author.
0169-5002/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0169-5002(95)00485-J
170
D. More
er al. /Lung
Cancer
13 (1995)
169-176
1. Introdwtion
Lung cancer is the leading cause of cancer deaths in Europe. Non small cell lung cancers (NSCLC) account for approximately 80% of all lung cancer cases. At the time of diagnosis approximately 30% of patients with NSCLC are eligible for surgery and have the best chance of a curative treatment. The main prognostic factors at the onset of treatment are, the stage of disease and performance status. There is great need for a tumor marker for the follow up and therapy control of these tumors. Carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and very recently CYFRA 21-l have been proposed for NSCLC. Carcinoembryonic antigen seems moderately useful in lung cancer clinical management [l], SCC is elevated in squamous cell carcinomas but has a lower sensitivity than CEA [2] and CYFRA 211 has proved, in preliminary report [3,4] to be a valuable marker. The aims of the current study were to assess the usefulness of CEA, CYFRA 21-l and SCC in NSCLC, to analyse the prognostic significance of a high tumor marker level and to determine the best combination of tumor markers. 2. Materials
and methods
2.1. Patients The current study was done retrospectively using 10.5 samples of frozen serum stored at -70” in our serum bank. Blood was sampled from patients at the time of diagnosis from 1987 to 1991. All patients had pathologically confirmed NSCLC. Staging of NSCLC was established according to the TNM UICC 1988 stage grouping. Fifty three of these 105 patients underwent surgery and thus were classified according to the post operative pTNM staging [5]. Survival data were obtained from Hospital files, General Practitioners and death certificates from City Hall registries. 2.2. Methods CEA was measured with a solid phase sandwich type immunoradiometric assay (IRMA) using a monoclonal antibody coated tube and a polyclonal ‘251-labelled antibody as a tracer (RIA-gnost” CEA,Behringwerke AG, Marburg, Germany). SCC was assayed with a solid phase IRMA using monoclonal antibodies (Abbott Laboratories, USA). CYFRA21-1 was measured with a solid phase sandwich typeIRMA using monoclonal antibodies. (ELSA-CYFRA21-1, Cis Bio international, France). The detection limit was 0.2 rig/ml for CEA, 0.5 rig/ml for SCC and 0.05 rig/ml for CYFRA21-1. Based on a specificity level of 95% and following manufacturers instructions, the upper normal values were, respectively at 3.3 rig/ml for CYFRA 21-1, 5 rig/ml for CEA and 2 rig/ml for SCC. 2.3. Statistics The tumor markers were studied as a continuous value, comparing patients with the lowest value to those with the highest value. Non parametric analysis were used: differences between two independent groups were determined by means of the
D. More et al. /Lung Cancer 13 (1995) 169-176
111
Mann-Whitney U test, differences between more than two groups were determined by means of the Kruskal-Wallis one-way analysis of variance. The survival of patients with normal and abnormal values were also compared. Actuarial survival rates were calculated from the time of treatment until the first of January 1992, using the method of Kaplan and Meier. The statistical comparison of survival was performed using the two tailed log-rank test offered by the Statview 4.1 Survival Tool package (Abacus concept Inc, California). The relative importance of multiple prognostic factors on survival was estimated using the Cox’s proportional hazards regression model. This data analysis was also performed using the Statview 4.1 Survival Tool package. Eight variables (TNM stage, histology, Performance status WHO/ECOG, age, sex, CYFRA 21-1 CEA and SCC level) were studied. Scores were assigned to 5 of the 8 variables (TNM stage, histology, Performance status WHO/ECOG, age,sex). CYFRA 21-1, CEA and SCC level were studied as continuous variables. A P-value of less than 0.05 was considered statistically significant. 3. Results
One hundred and five patients were studied, among them were 22 adenocarcinemas, 11 large cell carcinomas and 72 epidermoid carcinomas as defined by the WHO classification [6]. There were 96 males and 9 females, the mean age of patients was 61 years (range 36-83). Fifty three patients underwent a surgical treatment. After surgery, pathological study showed, seven adenocarcinomas, four large cell carcinomas and 42 epidermoid carcinomas. Patients clinical stages are listed in Table 1. The median assay value and interquartile range, for CYFRA 21-1 were 2.3 rig/ml (0.9-5.7) in the 105 patients, for CEA 3.7 rig/ml (2.3-7.2) for SCC 1.2 @ml (0.7-2.5). In the current group of 105 patients the CYFRA 21-1 level was above 3.3 r&ml in about 36% of cases (Confidence interval at 95%: 25-45%), whereas CEA showed a true positive result in 38% of the cases (Confidence interval at 95%: 28-48%) and SCC in 27% of the cases (Confidence interval at 95%: 17-35%).
1 Histologic types of the 105 patients studied
Table
Histology
Adenocarcinema
Large cell carcinoma
Epidermoid carcinoma
Stage I Stage II Stage III Stage IV
7 0 8 7
3 0 4 4
38 I 21 12
172
D. More et al. /Lung Cancer 13 (1995) 169-176
Table 2 The median and interquartile range of CYFRAZI-1, diagnosis
CEA (@ml) CYFRAZI-1 (@ml) SCC (@ml)
CEA and SCC according to the histological
Adenocarcinoma
Large cell carcinoma
Epidermoid carcinoma
5.45 (2.8-7.7) 2.35 (0.9-3.7) 1.2 (0.5-2.2)
4.15 (3.1-28) 2.7 (0.9-17.3) 1 (0.5-2.1)
3.2 (2.1-6.1) 2.15 (0.9-5.7) 1.35 (0.8-3)
3.1. CYFRA 21-1, CEA, SCC and histologic type (Table 2)
The serum CYFRA 21-l level was comparable in the different histological groups (Kruskal Wallis test: P = 0.79, Mann Whitney U test between epidermoid carcinomas and adenocarcinomas + Large cell carcinomas: P = 0.87). Considering surgical patients, serum CEA level was significantfy higher in the adenocarcinoma group when compared with the other histological groups (Kruskal Wallis test: P = 0,04, Mann Whitney U test: P = 0,04). The serum SCC level was comparable in the different histological groups (Kruskal Wallis test: P = 0.73, Mann Whitney U test between epidermoid carcinomas and adenocarcinomas + Large cell carcinomas: P = 0.23).The percentage of positive results of CYFRA 21-l) CEA and SCC and their relation to histology are presented in Table 3. 3.2. CYFRA 21-1, CEA, SCC and tumor stage
The CYFRA 21-l values were clearly dependant on tumor stage. A significant difference in the CYFRA 21-l level was observed between the 4 TNM stages of disease in the 105 patients (Kruskal Wallis test: P = 0.001, Mann Whitney U test between stages I+11 and III+IV P = 0.0007). This difference was also noted in the pTNM of the 53 surgical patients (Kruskal Wallis test: P = 0.001, Mann Whitney U test between post operative stages I+11 and III P = 0.003) (Fig. 1). The CEA value were also dependant on tumor stage. A significant difference in the CEA level was observed between the 4 TNM stages of disease in the 105 patients (Kruskal Wallis test: P = 0.005, Mann Whitney U test between stages I+11 and III+IV P = 0.03). However there was no statistical difference in the CEA level between the 3 surgical stages (Kruskal Wallis test: P = 0.7, Mann Whitney U test between post operative
Table 3 Percentage of positive results in the epidermoid carcinomas and adenocarcinomas % of positive tests
CYFRA 21-l
CEA
xc
Epidermoid carcinomas Adenocarcinomas
36% 31%
31% 59%
30% 19%
173
D. More et al. /Lung Cancer 13 (1995) 169-176 10
-
7.5
-
Fig. 1. Median
and interquartile
range of CYFRA
21-l according
to surgical
TNM
stage.
stages I+11 and III P = 0.6). There was no statistical difference in the SCC level between the 4 clinical stages (Kruskal Wallis test: P = 0.32, Mann Whitney U test between post operative stages I+11 and III+IV P = 0,88), but when the surgical stages where considered, this difference reached significance (Kruskal Wallis test : P = 0.04, Mann Whitney U test between post operative stages I+11 and III P = 0.03) 3.3. CYFRA 21-1, CEA, SCC, tumor size and nodal stage in surgical patients
Patients who presented more advanced tumors (T3 and T4) demonstrated
pmtbability
of sumival
higher
%
100 80 60
0
I 250
0
I 750
I 500 tim
Fig. 2. Kaplan Meier test P = 0.003).
survival
curves of the 105 patients
I 1000
I 1250
( W-1 according
to the level of CYFRA
21-I (Log-Rank
174
D. More
el al. /Lung
Cancer
13 (1995)
Table 4 Multivariate survival analysis. results of the Cox’s proportional Variable Stage of disease I and II III and IV Histology Epidennoid Adenccarcinoma and large cell carcinoma PS (WHO/ECOG) 0 and 1 2 and 3 Age <60 860
Assigned Coefficient score 0.945
hazards regression model
Chi2
P-value
RXP coefficient
0.359
6.925
0.0085
2.572
-0.535
0.333
2.579
0.1083
0.586
-0.072
0.316
0.052
0.8194
0.930
-0.714
0.335
0.0332
0.490
0.9769
1.019
0.0002 0.0028 0.2987
1.042 1.004 0.961
0 1 0 I
0 I -2.130
0 1
SCX
Male
Standard error
169-176
0.019
0.653
0.041 0.003 -0.040
0.011 0.001 0.038
0.0008
0 I
CYFRA21-I level CEA level SCC level
13 688 8.928 1.080
serum CYFRAZl-1 level when compared with patients with smaller tumors (Mann Whitney U test between post operative Tl+T2 and T3+ T4 P = 0.0006, Kruskal Wallis test: between the 4 T groups P = 0.0006). The nodal involvement was classified into 3 groups NO to N2. Patients who presented mediastinal lymph node involvement (N2) had higher serum CY FRA2 1- 1 level when compared with patients with smaller tumors (NO and Nl) but the difference was not significant (Mann Whitney U test P = 0.0506, Kruskal Wallis test between the 3 N groups P = 0.27). There was no impact of tumor size nor nodal stage on the CEA level (Tumor size, Mann Whitney U test between post operative Tl +T2 and T3+ T4 P = 0.64, Kruskal Wallis test: between the 4 T groups P = 0.88, Nodal stage, Mann Whitney U test between post operative NO+Nl and N2 P = 0.2, Kruskal Wallis test: between the 3 N groups P = 0.23). XC level were dependant on tumor size (Mann Whitney U test between post operative Tl+T2 and T3+ T4 P = 0.0013, Kruskal Wallis test: between the 4 T groups P = 0.0078) but not on the nodal stage (Mann Whitney U test between post operative NO+Nl and N2 P = 0.73, Kruskal Wallis test: between the 3N groups P = 0.88) 3.4. Survival analysis
There was a significant
difference in survival between patients with a normal
D. More et al. /Lung Cancer 13 (1995) 169-176
175
CYFRAZl-1 level and those with an elevated level (Log-Rank test P = 0.003) (Fig. 2). Patients with a high CEA serum level proved as well to have a shorter survival than those with a normal serum level (Log-Rank test P = 0.041) whereas SCC showed no impact on survival (Log-Rank test P = 0.186). The variables used in the Cox regression analysis are shown in Table 4; the estimated prognostic value of each variable in relation to overall survival among the 105 patients studied is expressed as a P value. Four variables (TNM stage, age, CYFRA 21-1 and CEA level) were found to be significant in the prediction of survival; CYFRA 21-1 level had the lowest P value (P = 0,0002). Histology, Performance status WHO/ECOG, sex and SCC level were not significant predictors of survival (P> 0.1). 4. Discussion In the clinical care of ‘non-small cell lung cancer’ there is a great need of signiticant variables able to predict metastatic spread and prognosis. These variables are important for assigning therapy and for clinical trial design and reporting. A consensus has been reached on some clinical, biological and therapeutic prognostic factors in non-small cell lung cancer [7]. Tumor markers are biological variables mostly used in the follow up of cancer patients. There is no general agreement on their use as prognostic factors. In the current study we attempt to correlate the level of CEA,SCC and CYFRA 21-1 to the tumor burden and to evaluate their usefulness as prognostic variables. CEA was identified in 1965. This tumor marker is widely used during the follow up of various tumor i.e.: Colorectal cancers, Breast cancer. In the current study CEA demonstrated higher values in adenocarcinomas (P = 0,04). The CEA level was slightly correlated with the TNM stage however there was no impact of the T stage nor the N stage on this level. In previous reports summarised by Ferrigno [8], CEA level usually increase in advanced stages. In the present study and in the literature CEA level is a predictor of survival. Squamous cell carcinoma (SCC) antigen, first described in carcinomas of the uterine cervix was also elevated in squamous carcinomas of the bronchus and nasopharynx. In the current study, SCC levels were comparable in all histologic types. SCC level increased with the size of the tumor and the pTNM stage however no impact of the nodal stage was demonstrated. No prognostic impact has been found (P = 0.186). This last point is in contrast with several other studies which reported a possible prognostic value for SCC level [2,9]. CYFRA 2 l-1 assay measures Cytokeratin 19 fragment. This new marker has been proposed in non-small cell lung carcinomas. CYFRA21-1 has been widely investigated by Pujol [3]. CYFRA 21-1 has been shown to be elevated in Non small cell lung carcinomas and particularly squamous cell carcinomas. In our study no difference was observed between the different histologic groups. The percentage of positive results of CYFRA 21-1 was 36% in the current study. This percentage is quite inferior than what has been previously reported (52% [3], 40% [lo], 47% [4]). This number of positive tests is quite comparable with that of CEA and is clearly superior than that of SCC. In the current study, the CYFRA 21-1 values were dependant on clinical and sur-
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gical tumor stages. The CYFRA 21-1 level increased with the tumor size (P = 0.0006) and the nodal stage. Although this last difference was not statistically significant in the current study, Pujol [3] has clearly demonstrated in a larger series, an impact of N stage on CYFRA21-1 level. Our study and others [3,1 l] showed in uni and multivariate analysis a correlation between CYFRA21-1 level and survival time, therefore CYFRAZl-1 seems to have a real prognostic value. The sensitivity of CYFRA21-1, CEA and SCC is low, these markers should not be used for the diagnosis of lung cancer, however when their level is increased at the time of diagnosis, they seem useful1 in the follow up of patients. Despite its dependence on tumor size SCC lacks of prognostic impact, is not dependant on TNM stage and is above the upper normal values in less than 30% of cases. From these data it seems that SCC has no clear clinical usefulness in ‘non-small cell lung cancers’. In contrast, both CYFRA21-1 and CEA are correlated with the tumor burden and are independant prognostic variables in the current population of patients. Therefore, these results may suggest to assay these two tumor markers in the work up of ‘non-small cell lung cancers’. However, prospectives studies are needed to establish the cost effectiveness of the combination of CEA and CYFRA21-1. Acknowledgements
Financial support was from INSERM, le Cancer.
Credits PHRC93,
Ligue Nationale
Contre
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