1368

Prognostic Significance of Serum CA 125 Antigen Assay in Patients with Non-Small Cell Lung Cancer Manuel Diez, M.D.,* Antonio Torres, M.D.,t Marina Polla’n, M.D.,$ Ana Gornez, M.D.,t Dolores Orfega, M.D.,§ Maria L. Maestro, M.D.,II Javier Granell, M.D.,* and Jose‘ L. Balibrea, M.D.t

Background. The serum levels of CA 125 tumor-as- sociated antigen in patients with lung cancer have been previously related to TNM stage, histologic type, and sur- vival rate. In the current study, the prognostic informa- tion provided by the CA 125 antigen assay was analyzed.

Methods. Preoperative serum of CA 125 antigen was determined in 137 patients with non-small cell lung cancer. The assay was performed by means of a solid- phase enzyme-immunoassay test. The influence of CA 125 serum level on postoperative outcome was studied by a multivariate analysis, performed with Cox’s propor- tional hazards regression model.

Results. Patients whose initial CA 125 level was higher than 15 U/ml had a 3.25-fold greater likelihood of relapse (95% confidence interval [CI], 1.7-6.21) (P < 0.001) and a 4.27-fold greater likelihood of death (95% CI, 2.42-7.55) ( P < 0.001) due to cancer than patients with lower values. For patients with serum levels over 15 U/ ml, the 36-month survival rate posttreatment was lower (67% versus 20%) (P < 0.001), as was the disease-free rate (64% versus 13%) (P < 0.001). After adjustment for TNM stages, histologic type, sex, and age, patients with CA 125 values over 15 U/ml continued exhibiting higher risk of relapse (hazard ratio, 2.2; 95% CI, 1.04-4.69) (P = 0.04) and higher risk of death (hazard ratio, 2.42; 95% CI, 1.29- 4.54) ( P = 0.006).

Conclusions. CA 125 is an independent prognostic factor of survival and tumor relapse in non-small cell lung cancer. The preoperative serum-level of CA 125 an- tigen is inversely correlated with the outcome figures.

From the *Department of General Surgery, Universidad de Al- Cali de Henares, Madrid; the Departments of tGeneral Surgery, GClinical Biochemistry, and IlNuclear Medicine, Hospital San Carlos, Universidad Complutense, Madrid; and the +Cancer Epidemiology Unit, National Center of Epidemiology, Instituto de Salud ”Carlos 111,” Madrid, Spain.

Address for reprints: M. Diez, M.D., Department of General Surgery, University Hospital, Alcali de Henares, Madrid, Spain.

Accepted for publication October 23, 1993.

The authors suggest that CA 125 be included in any fu- ture multifactorial analysis of survival. Cancer 1994; 73:1368-76.

Key words: lung cancer, CA 125, prognostic factors, stag- ing, tumor markers, prognostic index.

During the last two decades, no significant changes have been registered in the survival rates of patients with non-small cell lung cancer (NSCLC). Adjuvant chemoradiation therapy has been proposed as the best way to improve the results after curative resection.’ Differences between expected and actual outcome after curative resection according to TNM system, histologic type, or tumor grade predictions may be seen. The ne- cessity of finding new prognostic factors has been ad- voca ted.

Recently, great attention has been focused on the biology of lung cancer. The possibility that long-term results or response to treatment is based on the biologic factors inherent within the tumor cells is being con- firmed.*e3 New biologic prognostic factors are promot- ing Tumor markers are not a useful test for assisting diagnosis because of their low sensitivity and specificity.’-” However, tumor markers can provide in- formation relating to the biologic characteristics of the tumor cells. In a previous study, we observed that CA 125, an antigenic determinant recognized by the mono- clonal antibody OC125, was capable of offering prog- nostic information on survival in patients with NSCLC.” At a cutoff value of 15 U/ml, a relation with the resectability prognosis and the 24-month survival rate posttreatment was observed. Similar results were obtained by other author^.'^ Before we can incorporate this parameter into clinical practice as a staging system

Prognostic Value of CA 125/Diez e t al . 1369

Table 1. CA125 Serum Levels Categorized bv Patients’ Characteristics

25th-75th Mean SD Median percentile No. of cases > cutoff

Histologic type 1-16 23/84 (27.3%)

Adcnocarcinoma 20 59.6 8 2-19 12/43 (27.9%) Large cell 65.3” 86.8 28.3 11-90 7/10 (70%)

Squamous 18 43 5.3

TNM stage I , I I 10.9 17.9 5.2 1-12 16/80 (20%) Illa 16.8 23.6 7.5 1-27 13/32 (40%) Illb, IV 66* 110 16 5-59 13/25 (52%)

Male 21.8 55.4 5.7 1-17 35/126 (27.7%) Female 28t 33.1 20 5-32 7/11 (63.6%)

Agr i 50 yr 51 100 24.7 10-30 8/14 (57%) Age 2 50 yr 19* 45.5 6 1-17 34/122 (27.8%)

SD: h m d a r d dcviation

Sex

’ P < 0 01 ; t P < 0.05. Results are eiven as U / m l .

or as a guide to therapeutic decisions, a clarification of its prognostic value is needed.I4 Our aim in the current study was to assess the ability of preoperative serum CA 125 determination to provide information on the postoperative coursi? in patients with NSCLC, that is, overall survival rate and disease-free survival. We fo- cused on discriminating the information added by other predictors of prognosis.

Materials and Methods

One hundred thirty-seven newly diagnosed, histologi- cally proven patients with NSCLC (126 men, 11 women; mean age, 62 ? 11 years) treated between November 1988 and July 1992 were studied. No patients were in- cluded in our previous study.” They were submitted to our units for surgical treatment. All of them have been

Table 2. Predictors of Survival in Non-Small Cell Lung Cancer According to the Univariate Analysis

oh Surviving at time (mo) No. of No. of Hazard

Variable patients deaths 6 12 18 24 30 36 ratio c1 95% P-value

C A I 2 5 < 15 U/ml 95 23 98 88 76 69 67 67 1 > 15 U/ml 42 26 79 53 34 20 20 20 4.27 2.42-7.55 < 0.001

Squdmous 84 28 96 85 65 57 55 55 1

Large cell carcinoma 10 7 77 22 - - - - 4.76 2.04-1 1.8 < 0.001

Histologic type

0.788 0.57-2.08 Adenocarcinoma 43 14 90 76 72 60 60 60 1.09

T N M stage I 64 11 100 96 87 77 74 74 1 I I 16 3 100 92 83 70 56 41 1.26 0.35-4.53 0.727

< 0.001 ll la 32 15 93 68 54 37 37 - 4.21 lllb 18 13 79 50 7 7 - - 11.2 4.85-25.88 < 0.001 IV 7 7 57 0 35.07 11.07-102.9 < 0.001

Male 126 43 94 79 64 58 56 56 1 Female 11 6 80 57 57 19 19 - 2.25 0.95-5.32 0.064

51)-64 65 18 98 84 68 62 59 59 1 < 50 14 8 69 44 35 35 - - 2.77 1.20-6.41 0.017 > 65 58 23 93 78 65 53 53 53 1.24 0.67-2.31 0.497

1.91-9.29

Sex

Age (yr)

CI: conhdence interval.

1370 CANCER March 1, 1994, Volume 73, No. 5

Table 3. Kaplan-Meyer Estimates of Survival Rates for the Different Predictor Variables Stratified According to CA125 Level

% Surviving at time (mo) No. of No. of

Variable patients deaths 6 1 2 18 24 30 36 P value

Histologic type Squamous

CA125 < 15 CA125 > 15

Adenocarcinoma CA125 < 15 CA125 > 15

CAI25 < 15 CAI25 > 15

Large cell carcinoma

TNM stage 1

CA125 < 15 CA125 > 15

CA125 < IS CA125 > 15

CA125 < 15 CA125 > 15

CA125 < 15 CAI25 > 15

CA125 < 15 CA125 > 15

I I

llla

lllb

1v

Sex Male

CA125 < 15 CA125 > 15

CAI25 < 15 CA125 > 15

Female

Age (yr) 50-64

CA125 < IS CAI25 > 15

CA125 < 15 CA125 > 15

CAI25 < 15 CA125 > 15

< 50

> 65

65 23

31 12

3 7

54 10

10 6

19 13

9 9

3 4

91 35

4 7

48 17

6 8

41 17

15 13

7 7

1 6

8 3

0 3

7 8

5 8

3 4

22 21

1 5

9 9

3 5

11 12

100 87

97 61

100 67

100 100

100 80

94 91

100 64

100 25

99 82

100 71

100 92

80 63

100 77

93 66

82 49

100 17

98 88

100 53

78 51

67 38

100 25

88 57

100 36

95 46

60 31

85

75 38

82 32

67 -

90 70

100 53

63 38

17 25

-

-

75 34

100 36

82 23

40 31

75

70 20

71 32

67 -

82 47

100 53

54 13

17 -

- -

70 23

50 36

74 23

40 31

69

67 20

71 32

67 -

79 47

100 53

54 13

17 -

- -

68 23

50 -

70 23

40 31

69

67 20

71 32

67 -

79 47

100 53

54 13

- -

-

-

68 23

50 -

70 23

40 31

69

0.001

0.03 1

0.074

0.105

< 0.001

0.100

0.297

0.222

< 0.001

< 0.001

< 0.001

0.601

0.002 65 41 10 10 10

consecutively studied and followed up prospectively. No patient underwent chemotherapy or radiation ther- apy before surgery. Patients who died of complications after surgery during this period (operative death) (five patients) have not been included. Histopathologic diag- nosis was performed in accordance with the World Health Organization classification of lung tumors:I5 84

(61.3%) patients had squamous carcinoma; 43 (31.4%), adenocarcinoma; and 10 (7.3%), large cell carcinoma. Pathologic material has been specially revised for this study by the same pathologist. TNM staging16 was per- formed by correlating the operative and histologic find- ings: 64 (46.8%) patients with TNM Stage I disease; 16 (11.7y0), Stage 11; 32 (23.3%), Stage IIIa; 18 (13.1yo),

Prognostic Value of CA 125/Diez e t al . 1371

FOLLOW UP (Mth8) 1 1 1 - CAI26 cl6 Ulml - CA126 ~16 Ulml I

~~~~ ~

Figure 1. Overall survival rate in squamous carcinoma and adenocarcinoma by CA 125 serum level.

Stage IIIb; and 7 (5.1%), Stage IV. All patients had preoperatory bronchoscopy, chest radiographs, and a thoracoabdominal computed tomography scan. Medias- tinoscopy was not performed routinely. Head com- puted tomography scans and radionuclide scans of liver or bone were performed only when indicated by clinical or biochemical abnormalities. Careful complete sam- pling of mediastinal lymph node groups was performed routinely in all patients before resection of the primary lesion. Resection was considered to be curative when the primary tumor mass was excised along with all posi- tive hilar and mediastinal lymph nodes and with histo- logically proven negative margins. This included pa- tients with TNM Stage I and I1 disease. All patients with Stage IIIa disease included in the current study also ful- filled these criteria. Patients with Stage IIIb disease had direct tumoral invasion of mediastinal nonresectable structures. Three patients with TNM Stage IV disease with brain metastasis underwent metastasis resection as a first step, followed by resection of the primary tumor. In the other patients, Stage IV disease was due to pleural carcinomatosis or intrapulmonary metastasis. Among potentially curable patients, adjuvant radiation therapy was administered to patients with Stage IIIa disease with chest wall involvement. Where there was relapse, locoregional disease was preferentially treated with palliative radiation therapy; chemotherapy was offered to any patient with a good performance status and disseminated disease.

All these patients were assayed for serum CA 125 before surgery. CA 125 was determined by a commer- cially available solid-phase enzyme immunoassay kit

(Roche, Basel, Switzerland). The test was applied ac- cording to the manufacturer’s instructions. The samples were always processed within 3 days after extraction.

During follow-up, two patients died due to an unrelated cause 3 and 16 months after surgery, respec- tively. Two patients were lost to follow-up. In those four cases, no tumor relapse had been detected. All the remaining patients were followed up to last visit or death. At the time of our analysis, 46 patients had died. Tumor relapse was detected in 40 subjects (36%) among those operated on with Stages I, 11, and IIIa dis- ease (111 patients). Median time from study entry to date of last visit for these 91 living patients was 22 months (range, 5-51 months).

For statistical analysis, the Mann-Whitney U test was used in two-group comparisons, whereas the Krus- kal-Wallis nonparametric analysis of variance was ap- plied for comparisons of three or more groups. Survival and likelihood of tumor relapse related to initial serum CA 125 values was studied using the Kaplan-Meier method, and differences between subgroups of patients were compared with Mantel’s log-rank test. Survival time was calculated from the time of surgery to last contact or date of death. Disease-free survival time was calculated as the disease-free interval beginning from the date of surgery. For statistical analyses in the current study, locoregional and distant recurrences were included in the same group. Categorization of CA 125 was effected using the cutoff value of 15 U/ml, as in previous studies.I2 This value offered the best bal- ance sensitivity-specificity ratio in the receiver operat- ing-characteristic curve. To assess the relative value of CA 125, additional factors were analyzed in conjunc- tion with the markers for sex, age, TNM classification, and histologic type.

The relative importance of multiple prognostic fac- tors on survival and disease-free survival duration was estimated using Cox’s proportional hazards regression m0de1.I~ For survival analysis, all patients were studied, whereas for disease-free survival analysis, only patients with Stage I, I1 or IIIa tumor were included. The crude effect of each predictor was evaluated using unadjusted hazard ratios as an estimate of relative risk. Thereafter, all predictors were included in a multivariate approach. We retained the non-statistically significant variables approach in the model for two reasons: (1) the aim of the analysis was to estimate the adjusted effect of CA 125 by controlling for other variables studied capable of modifying survival and disease-free survival time and (2) the sample size led to the study’s statistical power being small, meaning that lack of statistical significance does not necessarily entail absence of effect. CA 125 was considered as a dichotomous variable, with 15 U/ ml as the cutoff value. Other models with CA 125 as a

1372 CANCER March I , 1994, Volume 73, No. 5

continuous variable and as a three-category variable (less than 15 U/ml, 15-29.9 U/ml greater than or equal to 30 U/ml) were fitted but did not improve goodness of fit. In both analyses, the two-way interaction effects between CA 125 and the other predictors were exam- ined.

Results

Univariate Analysis

Concentration of serum CA 125 and distribution of re- sults according to patients' characteristics are shown in Table 1. Univariate analysis showed that CA 125 values differed significantly among subgroups defined by the TNM classification, histologic type, sex, and age. A di- rect relationship between CA 125 serum values and TNM classification was detected, with the highest val- ues achieved within the more advanced TNM stages. By histologic type, large cell carcinomas showed the highest serum values. Women and patients younger than age 50 years exhibited the highest concentration, although these results are not fully representative due to the presence of more advanced cases in these groups.

The overall 36-month survival rate was 54%. This result was related significantly to the five clinicopatho- logic factors analyzed: TNM classification, histologic type, sex, age, and CA 125 serum level (Table 2). Pa- tients whose initial CA 125 level was higher than 15 U/ml had a 4.27-fold greater risk of dying (95% CI, 2.42-7.55) ( P < 0.001) due to the cancer than patients with lower values. The 36-month survival rate post- treatment was lower for patients with serum levels greater than 15 U/ml (67% versus 20%) ( P < 0.001). Prognostic value of CA 125 was confirmed when the above factors were stratified by CA 125 level. In any category, the best survival rate was obtained by patients with serum CA 125 below 15 U/ml (Table 3). Compari- son of survival rates among the groups defined by histo- logic classification showed highly significant results in squamous carcinomas and adenocarcinomas. For these tumors, the 36-month survival rate was 67% for pa- tients with CA 125 values up to 15 U/ml versus 25% for those with values over that cutoff ( P < 0.001) (Fig. 1). It should be noted that although the subgroup with large cell carcinoma was small (10 patients) and the follow-up was especially short (no patient was followed up for longer than 24 months), the 24-month survival rates associated with CA 125 values below and above 1.5 U/ml differed significantly (66% versus 0%) ( P < 0.05)(Fig. 2). Overall disease-free survival rate post- treatment among those patients with TNM Stage I, 11, or IIIa disease was 50%. The results were again influenced by the histologic type, TNM classification, sex, age, and

SURVIW (%I - - . 100'

60 -

- - - - -- - 80 -

- - -. .. - - 40 -

- - _. - 20- -

0 1 1 " ' 1 ' ' 1 ' I I L I I I I I I I I

8 12 18 24 FOLLOW UP (fMtlth8)

- CA125 (1 Ulml - C A W ~16 U/ml

Figure 2. Overall survival rate in large cell carcinoma by CA 125 serum level

CA 125 serum level (Table 4). Patients whose initial CA 125 level was higher than 15 U/ml had a 3.25-fold greater risk of relapse (95% CI, 1.7-6.21) ( P < 0.001). The 36-month disease-free rate was lower for patients with CA 125 serum values above 15 U/ml(64% versus 13%) ( P < 0.001). Stratification of these factors by CA 12.5 level showed lower disease-free rates for categories whose initial value was greater than 15 U/ml (Table 5). According to histologic type, the influence of CA 125 level was statistically significant among squamous carci- nomas and adenocarcinoma (62% versus 30%) (36- month disease-free rate) ( P < 0.001) (Fig. 3) and large cell carcinomas (66% versus 0%) (24-month d' sease- free rate) ( P < 0.001) (Fig. 4).

Multivariate Analysis

Squamous carcinomas and adenocarcinomas were taken as the reference group for histologic type, because no differences were found between these categories re- garding the likelihood of death or relapse (Tables 2 and 3). Similarly, Stages I and I1 were analyzed jointly.

Tables 6 and 7 show the results of the two multi- variate models, survival and disease-free survival, re- spectively. Interaction terms did not significantly im- prove either of these final models. CA 125-once ad- justed for other prognostic factors-revealed itself to be an important predictive factor in both cases. Among patients with CA 125 levels above 15 U/ml, the risk of relapse is 2.24-fold higher than among patients sharing similar pathologic findings, the same sex, and equiva- lent age yet having CA 125 levels lower than the cutoff.

Prognostic Value of C A 125 /D iez et al . 1373

Table 4. Predictors of Disease-Free Survival in Non-Small Cell Lung Cancer According to the Univariate Analysis 010 Surviving at time (mo)

No. of No. of Hazard Variable patients relapses 6 22 28 24 30 36 ratio CI 95% P value

CAI25 < 15 > 15

Squamous Adenocarcinoma Large cell cancer

I I I IIla

Sex Male Female

t ilstologlc type

T h M stagr

Age (vr)

< 50 > 65

50-64

83 29

68 36

8

64 16 32

103 9

54 10 48

24 16

25 10 5

19 5

16

35 5

14 7

19

94 77

96 91 29

96 85 79

91 75

92 66 92

81 58

78 80

0

87 77 50

76 60

83 40 69

72 36

64 72

72 67 46

65 45

68 26 62

68 27

59 44

67 67 39

62 22

61

59 -

64 27

54 44

61 67 39

58 -

61

52 -

64 1 13 3.25

54 1 44 0.88

4.03

61 1 44 1.36 _ - 2.72

58 1 2.39

61 1 - 3.71 52 2.67

1.7-6.21

0.42-1.84 1.52-10.68

0.50-3.69 1.38-5.37

0.93-6.15

1.4-9.82 1.06-6.73

P < 0.001

0.736 0.005

0.540 0.004

0.071

0.008 0.037

CI conhdence interval

Moreover, this difference is greater still for the risk of death (2.42). Additionally, inverse dose-response rela- tionship was found between CA 125 level and survival disease-free time (hazard ratio for a raise of one unit in thelevel of CA 125 equals 1.016; 95% CI, 1.002-1.029).

Among the other predictors, TNM stage and histo- logic type proved the most important. Age and sex did not exhibit statistical significance. The hazard ratio for women was appreciably high, but the small number of women in the study worked against any significant ef- fect being detected.

Discussion

CA 125 was initially described as an ovarian cancer-as- sociated antigen." Elevated serum levels are observed in more then 80% of patients with epithelial ovarian carcinomas, and the assay deserves continued evalua- tion for the purposes of monitoring and early diagno- sis." Recently, CA 125 has been assayed in NSCLC,10,12,13~20 although the results have not yet been as well recognized as those of carcinoembryonic anti- gen. This latter marker remains the gold standard tumor marker for NSCLC, though the results obtained are not encouraging.'-" According to recent publications, in NSCLC, CA 125 possesses a low sensitivity, ranging between 62% and 34%.'0~12~13 However, it has qualities that characterize i t as a good tumor marker, namely, significant difference between healthy control subjects, nonmalignant pulmonary conditions, and patients with

lung cancer; serum concentration directly proportional to tumor TNM stage; and good specificity and good positive predictive value. The same studies have indi- cated that before treatment, CA 125 may also be pro- posed as a tool for predicting the course of the disease, although no adjustments were made for the influence of other

TNM stage is recognized as the main prognostic factor in NSCLC.' Histologic classification, sex, and age offer additional prognostic information. Variation of the serum concentration of CA 125 by those factors have been confirmed in the current study. We sought to test the hypothesis that the information provided by the CA 125 assay could not simply reflect tumor load, stage, or histologic type, but could be an independent prognostic factor per se.

Our data prove the prognostic ability of CA 125 in NSCLC and the independence of this information from that provided by the other factors. Only TNM stage, histologic subtype, and CA 125 demonstrate indepen- dent prognostic value. In the univariate analysis, pa- tients with CA 125 serum concentration higher than 15 U/ml showed a 4.27-fold greater risk of relapse and a 3.25-fold greater risk of death due to lung cancer than those patients with lower serum values. When the other variables included in the study were considered in the multiple regression method, the hazard ratios were 2.2 and 2.42, respectively. This method allows for the si- multaneous assessment of the effects of several factors. The difference in the hazard ratio, as between the uni-

1374 CANCER March 2, 1994, Volume 73, No. 5

Table 5. Kaplan-Meyer Estimates of Disease-Free Survival Rates for the Different Predictor Variables Stratified According to CA125 Level

% Surviving at time (mo)

Variable No. of patients No. of deaths 6 12 18 24 30 36 P value

Histologic type Squamous

CA125 < 15 CA125 > 15

Adenocarcinoma CA125 < 15 CAI25 > 15

CAI25 < 15 CA125 > 15

Large cell carcinoma

T N M stage I

CA125 < 15 CA125 > 15

CAI25 < 15 CA125 > 15

CAI25 < 15 CA125 > 15

I1

Illa

Sex Male

CA125 < 15 CA125 > 15

CA125 < 15 CA125 > 15

Female

Age (yr) 50-64

CA125 < 15 CAI25 > 15

0.125 < 15 CA125 > 15

CA125 < 15 CA125 > 15

< 50

> 65

52 16

28 8

3 5

54 10

10 6

19 13

79 24

4 5

44 10

3 6

35 13

16 9

7 3

1 4

9 4

1 4

8 8

22 13

2 3

10 4

2 4

11 8

98 94

93 86

67 53

96 1 00

100 63

89 64

95 82

100 60

98 71

67 67

94 85

83 64

80 86

67 -

88 90

88 63

61 32

82 59

67 60

89 71

33 44

76 62

73 32

74 64

67 -

77 43

88 31

55 32

73 38

67 30

75 36

33 22

73 46

70 16

68 64

67 -

72 43

88 31

5s 16

71 29

33 30

67 36

33 22

73 23

64 16

68 64

67 -

66 43

88 31

55 16

66 29

33 -

67 36

33 22

63 23

64 16

68 64

67 -

66 43

88 31

55 16

66 29

33 -

67 36

33 22

63 23

0.012

0.550

0.118

0.194

0.020

0.107

0.002

0.372

0.044

0.853

0.038

variate and multivariate analyses, shows the influence of the other predictors on the results of CA 125 and therefore the exact prognostic ability retained by this factor. According to the mathematical predictive model, male patients with a CA 125 serum value greater than 15 U/ml, TNM Stage IIIa disease, and squamous carci- noma have a 7.76-fold higher risk of death due the cancer and a 4.57-fold higher risk of relapse than male patients of the same age with lower serum concentra- tion, TNM Stage I or II disease, and squamous carci- noma. The individualized risk can be calculated easily by multiplying the hazard ratio of the factors affecting that patient. Despite the fact that the model furnishes

estimates for the calculation of these differences in women, differences should not be taken into account given the low number of women involved. The same holds true for patients with large cell carcinoma, though the model proved capable of detecting a significantly higher excess risk of death and relapse for this category.

In the current study, the hazard ratio associated with elevated serum CA 125 concentrations was high for risk of relapse and death. We did not attempt to disclose the influence of treatment modalities on sur- vival: that type of study contains many confounding factors and requires a larger population. However, death due to cancer may be more influenced by chemo-

Prognostic Value of CA 125/Diez e t a l . 1375

401 - .

I 1 I

. -

2o t 8 12 18 24 so 58

' ' I I 1 I ' I ' I ' I ' O-ll I ' I ' I I I

FOLLOW UP (months)

I - CAI26 416 Ulml - CAl26 b16 Ulml 1 Figure 3. Disease-free rate in squamous carcinoma and adenocarcinoma by C A 125 serum level. TNM Stages IIIb and IV have not been considered.

therapy, radiation therapy, or supportive treatment. We believe that the prediction of relapse possibilities is a purer reflection of the value of a prognostic factor. In the case of CA 12.5, the information provided by the assay should be attributed to the fact that this marker closely reflects the biologic behavior of the tumor cell.

The identification of prognostic factors is useful not only to help define clinical management, but also to facilitate communication between physicians, to pro- vide a basis for stratification and analysis of treatment

DISEASE FREE SURVIWL (51

Table 6. Results of the Cox Proportional Regression Model for Survival

Variable Hazard ratio CI 95% P value

C A I 2 5 < 15 U/ml > 15 U/ml

Histologic type Squamous + adenocarcinoma Large cell carcinoma

TNM stage I + I1 IIIa IlIb IV

Male Female

Sex

Age (Yr) 50-64 < 50 z 65

1 2.42

1 5.10

1 3.21 9.75

51.76

1 2.24

1 1.24 1.59

1.29-4.54 0.006

1.76-14.83 0.003

1.41-7.29 0.005 4.11-23.13 < 0.001

15.97-167.7 < 0.001

0.80-6.27 0.123

0.51-3.02 0.636 0.82-3.09 0.174

C1: confidence interval. Each variable is adiusted by the others included in the model

results in prospective studies, and to provide some prognostic information for patients and their fa mi lie^.'^ Efforts to define a set of prognostic determinants im- portant for lung cancer have continued throughout the last decade and have included clinical characteristics

Table 7. Results of the Cox Proportional Regression Model for Disease-Free Survival

Variable Hazard ratio CI 95% P-value

C A 125 < 15 U/ml 2 15 U/ml

Histologic type

1 2.2 1.04-4.69 0.04

Squamous + adenocarcinoma 1 Large cell carcinoma 4.41 1.47-13.26 0.008

I + I1 1 TNM stage

8 l2 la FOLLOW UP (month4

- CA126 c l 8 Ulml - CAQO Ulml C J

24

Figure 4. Disease-free rate in large cell carcinoma bv C A 125 serum 1e;el. TNM Stages 1111) and IV have not been considered.

IIIa 2.08 1.01-4.28 0.047

Male 1 Female 1.98 0.66-5.88 0.221

50-64 1 < 50 1.87 0.59-5.93 0.290 z 65 1.35 0.63-2.91 0.443

Sex

Age

Each variable is adjusted by the others included in the model. TNM stages lllb and IV have not been considered.

1376 CANCER March 1, 1994, Volume 73, No. 5

and pathologic aspects in addition to a large number of laboratory parameter^.^-' TNM system for anatomic tu- mor staging should continue as a reference patient clas- sification system. Nevertheless, methods for the de- scription of tumor aggressiveness, such as CA 125 as- say, are rapidly expanding. In the future, a score derived using a multiple-regression approach that com- bines anatomic description of tumor spread and the as- sessment of tumor aggressiveness may generate a pa- tient-specific prognostic index.I4 The possibility of indi- vidualized patient management based on serum CA 125 antigen determination is attractive. However, in vi- tro and clinical studies should first help investigate the chemoradiation therapy response of tumors expressing the marker.

Neither the underlying reason for the predictive value of CA 125 nor the junction between CA 125 ex- pression and biologic behavior of cells is known. By quantification of CA 125 in cytosol of NSCLC tumors, we know that concentration of the marker is an individ- ual characteristic in certain tumor cells.” In cultured ovarian cell lines, Marth et al. analyzed the relationship between expression of CA 125 and cell cycle.” CA 125 expression was associated predominantly with the Go/ G, phase of the cycle and was dependent on cell den- sity. Tumors with a high proportion of cells in the S and G,/M phases showed suppressed CA 125 expression. We do not know if that observation is also valid for lung cancer. Analysis of CA 125 expression in cultured lung cancer cell lines and correlation with pathologic charac- teristics, tumor grade, cellular proliferation markers, and molecular markers is needed.

In conclusion, CA 125 is an independent prognostic factor of survival and tumor relapse in NSCLC. On the basis of the current findings, we suggest that CA 125 be included in a future multifactorial analysis of survival and used as an aid in the staging system.

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