- Email: [email protected]
Evaluation of serum CA 125 levels in the monitoring of ovarian cancer
Ludmir et al.
5. Sbarra AJ, Michlevitz H, Selvaraj RJ, et a!. Correlation between amniotic fluid optical density and LIS ratio. Obstet Gynecol 1976;48:613. 6. Touchstone JC, Levin SS, Dobbins MF, Matthews L, Beere PC, Gabbe SG. (3-sm-phosphatidyl) cholines (lecithins) in amniotic fluid. Clin Chern 1983;29:1951. 7. Gluck L, Kulovich MV, Borer RC, Brenner PH, Anderson GG, Spellacy WN. Diagnosis of the respiratory distress syndrome by amniocentesis. AM J 0BSTET GYNECOL 1971; 109:440. 8. Haney D, Parkinson CE, Campbell S. Risk of respiratory distress syndrome. Lancet 1975;1:42. 9. Herbert WNP, Tyson J, Jimenez JM. Severity of respiratory distress syndrome with low lecithin: sphingomyelin ratio. Obstet Gynecol 1981 ;57:426.
July 1987 Am J Obstet Gynecol
I 0. Gab be SG. Recent advances in the assessment of fetal lung maturity. J Reprod Med 1979;23:228. II. Garite TJ, Freeman RK, Nageotte MP. Fetal maturity cascade: a rapid and cost effective method for fetal lung maturity testing. Obstet Gynecol 1986;67:619. 12. Maniscalco WM, Finkelstein JN, Parkhurst AB. De novo fatty acid synthesis in developing lung. Biochim Biophys Acta 1982;7ll:49. 13. Groener JEM, Van Rozen AJ, Cibelens DW. Cholesteryl ester transfer activity: localization and role in distribution of cholesteryl ester among lipoproteins in man. Atherosclerosis 1984;50:261.
Evaluation of serum CA 125 levels in the monitoring of ovanan cancer Ignace B. Vergote, M.D.,* Ole P. Bf
Key words: CA 125 serum levels, monitoring, ovarian cancer The natural history of ovarian cancer is characterized by intra-abdominal spread, which hinders early diagnosis and accurate monitoring of the disease. During recent decades a large number of antigens have been detected in ovarian cancers. Bast et a!.' developed a promising assay based on a murine monoclonal antibody (OC 125), reacting with the antigen CA 125, which is expressed by more than 80% of nonmucinous epi-
From the Departments of Gynecologic Oncology and Pathology and the Central Laboratory of The Norwegian Radium Hospital. Received for publication October 3, 1986; revised january 8, 1987; accepted February 6, 1987. Reprint requests: Ignace B. Vergote, M.D., Department of Gynecologic Oncology, The Norwegian Radium Hospital, Montebello, N-0310, Oslo, Norway. *Fellow of the NATO Research Foundation and the Belgian Fund for Scientific Research.
88
thelia! ovarian cancers. The objectives of this study were to investigate the prognostic value of preoperative and postoperative CA 125 serum levels in ovarian cancer, to determine the value of CA 125 in monitoring the disease, and to assess the correlation between CA 125 serum levels and histologic type and degree of differentiation.
Material and methods A total of 606 serum samples from 227 patients with ovarian cancer have been tested for CA 125. The samples were obtained between February 1983 and February 1985 and stored at - 20° C until they were analyzed. All patients had follow-up until July 1986. The results of theCA 125 test were not known at the time of treatment. Clinical staging was performed according to the sys-
Volume 157 Number I
CA 125 in monitoring of ovarian cancer
89
Table I. Preoperative and postoperative CA 125 serum levels in ovarian cancer patients CA 125 level
Preoperative Postoperative* Without residual tumor <2 em Residual tumor ;;.2 em Residual tumor
n
>35 U/ml (n)
37
34
57 10 46
9 2 42
I
Median (Uiml) 439 1St 24t 187
I
Range (Uiml) 10-30800 2-203 6-1607 6-18400
*Samples were obtained 3 to 6 weeks after primary operation and before the start of chemotherapy. tp < 0.001 compared with the preoperative group and the postoperative group with ;;.2 em. of residual tumor.
terns adopted by the international Federation of Gynecology and Obstetrics.• This series included 71 patients in Stage I, 13 in Stage II, 108 in Stage III, and 35 in Stage IV disease. The principles of therapy consisted of primary operation followed by cytotoxic chemotherapy with cisplatin, cyclophosphamide, Thiotepa, or carboplatin or by instillation of radioactive phosphorus. Evaluation of response to treatment was based on clinical observations and radiologic data. Response to treatment was evaluated according to the recommendations of the World Health Organization.' Registration of disease progression requires a 25% or more increase in the size of the existing lesions or the appearance of a new lesion. Disease regression requires at least a 50% decrease in tumor size for at least 4 weeks for partial response and a disappearance of all clinical signs of malignancy for complete response. All relapses were confirmed by histologic or cytologic findings. One of the authors (V. M. A.) reviewed all the slides. The results of the CA 125 investigation were not known at that time. Histologic classification was performed with the criteria defined by the World Health Organization.< One hundred sixteen tumors were serous, 31 mucinous, 22 endometrioid, 12 clear cell, 12 undifferentiated, 18 mixed, and 19 unclassifiable carcinomas. One patient had a malignant Brenner tumor, and three had nonepithelial tumors. CA 125 assays. CA 125 was measured by an immunoradiometric ("sandwich") assay (Abbott CA 125 radioimmunoassay, Abbott Laboratories, North Chicago, Illinois), performed according to the instructions of the manufacturer. This kit uses antibody OC 125 bound to polystyrene beads and radiolabeled OC 125 to measure the amount of antigen bound from samples and standards during incubation. The interassay coefficient of variation was 6% with the control sera of the kit. The reference limit of 35 U/ml, as proposed by Bast et al., 1 was verified in a small reference population. This group consisted of 45 patients with benign diseases. Only one patient in this group had a slightly elevated value. In serial analysis a doubling or halving
of the CA 125 levels was considered a significant increase or decrease. Sampling. Serum samples were obtained at the moment of referral to The Norwegian Radium Hospital. Most patients are referred in the postoperative phase or when they develop a relapse. This explains why we were unable to study the CA 125 levels in all patients during the entire treatment period. Serum samples were available from 37 patients before staging laparotomy and from 113 patients after operation. Sampling was performed in the week before laparotomy in the former group and 3 to 6 weeks after operation and before the start of chemotherapy or radiotherapy in the latter group. The postoperative group consisted of 56 patients with residual disease and 57 patients without any. The group of patients with preoperative measurements was small because the majority of patients were referred to our hospital after primary operation. In 112 patients with epithelial cancer serial measurements were performed during chemotherapy. Thirteen cases were excluded ( 11 with initially normal CA 125 levels and two with nonepithelial tumors). Serum samples were assessable at the moment of relapse in 29 patients who previously had received chemotherapy but had been free of treatment for at least 3 months. Second-look laparotomy was performed in 21 patients without clinical or radiologic evidence of disease. Eleven patients were free of tumor after the primary operation. Serum samples were collected in the week before second-look operation. Statistical analysis. For statistical analysis the x• test and the Wilcoxon test were used. 5 When no statistical analysis is mentioned, the Wilcoxon test was used. Results
CA 125 levels in preoperative and postoperative patients. Table I summarizes the preoperative and postoperative serum CA 125 levels. Postoperative CA 125 levels were significantly lower in patients without residual tumor and in patients with <2 em of re-
90
Vergote, B0rmer, and Abeler
July 1987 Am J Obstet Gynecol
Table II. Serum CA 125 levels in ovarian cancer patients with evidence of disease* in relation to histologic type CA 125 level Histologic type Epithelial tumors Serous cystadenocarcinoma Mucinous cystadenocarcinoma Endometrioid carcinoma Clear cell carcinoma Mixed carcinoma Undifferentiated carcinoma U nclassifiable carcinoma Mixed mesodermal tumor Carcinosarcoma
n
>35 Ulml (n)
68 4 8 6 10 4 12 1 1
61 3 6 3 9 3 11 1 1
346 47t 308 46:j: 286 309 333 395 48
7-30800 15-157 6-1727 12-329 15-3316 10-1000 6-1607
98 (86%)
266
6-30800
114
Total
Median (Uiml)
I
I
Range (Uiml)
*Preoperative and postoperative patients with evidence of disease at the moment of sampling and patients with untreated relapse. Patients who had more than one sample assessable have the first sample included. tp = 0.02 compared with serous cystadenocarcinoma. :j:p = 0.015 compared with serous cystadenocarcinoma.
Table III. Serum CA 125 levels in ovarian cancer patients with evidence of disease* in relation to degree of differentiation CA 125 level Differentiation
n
>35 Ulml (n)
Borderline Grade 1 Grade 2 Grade 3
4 8 26 76
3 5 24 66
I
Median (Uiml) 57t 53:j: 242 387
J
Range (Uiml) 7-157 14-358 30-4278 6-30800
*Preoperative and postoperative patients with evidence of disease and patients with untreated relapse. tp = 0.027 compared with values for grade 2 and 3 lesions. :j:p = 0.007 compared with values for grade 2 and 3 lesions.
sidual disease compared with the two other groups (preoperative or postoperative with >2 em of residual disease; for each group p < 0.001). There was no significant difference between the latter two groups or between the former two groups (p = 0.15 and p = 0.57, respectively). In 34 of 3 7 patients preoperative CA 125 values were elevated. One patient with Stage I disease, 24 with Stage Ill, and nine with Stage IV had elevated CA 125 levels. Three patients with Stage III had values within the normal range (two serous and one undifferentiated carcinoma). The prognostic value of preoperative CA 125 levels was evaluated in 36 patients with Stage III or IV disease. The CA 125 levels tended to correlate inversely with survival (median follow-up 26 months; p = 0.06). The prognostic value of postoperative CA 125 levels (sampled 3 to 6 weeks after staging laparotomy) in patients without residual tumor was evaluated in 57 cases. A raised postoperative CA 125 serum level implied a
bad prognosis, since four of eight patients with elevated levels had relapse, whereas only five of 49 patients with normal levels had relapse (median follow-up 24 months; x2 , p < 0.02). Histologic type and differentiation. The relation between histologic type and serum CA 125 levels in patients with evidence of disease is shown in Table II. CA 125 levels were significantly higher in serous cystadenocarcinomas than in mucinous and clear cell carcinomas (p = 0.02 and p = 0.015, respectively), but no significant difference was observed when serous cystadenocarcinomas were compared with the other epithelial tumors. Grade 2 and 3 tumors showed higher CA 125 serum levels than borderline and grade 1 tumors (p = 0.027 and p = 0.007, respectively). There was no significant difference between the former two groups (Table III). CA 125 monitoring profiles during chemotherapy. Serial measurements were performed during chemotherapy in 112 patients with epithelial cancer. These
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CA 125 in monitoring of ovarian cancer
91
Table IV. Variation inCA 125 levels with disease status in response to chemotherapy Disease status Antigen level*
Complete response
Partial response
Stable disease
Progression
Decreased Remained unchanged Increased
16 0 0
28 0 0
3 13 0
2 3 36
Total
16
28
16
41
*Doubling or halving of CA 125 levels was considered a significant increase or dectease.
findings are presented in Table IV. CA 125 levels correlated with the clinical course in 93 of 10 I cases (92%). A rising CA 125 level was always associated with disease progression (n = 36). In 16 of these patients a significant increase in CA 125 was observed at least . 1 month before clinical evidence of progression ( 1 to 8 months, median 3 months). Despite obvious clinical progression, two patients had decreasing CA 125 values (one serous and one clear cell carcinoma). CA 125 values normalized in 14 of 16 patients with complete response. Twelve of the 14 patients had a relapse during the observation period. During partial remission, CA 125 values normalized in nine of 28 patients, whereas CA 125 levels remained elevated in all patients with stable or progressive disease. CA 125 measurements were performed 4 weeks after the first course of chemotherapy in 14 patients with partial or complete remission. All patients had a decrease in CA 125 levels ranging from 30% to 95% (mean 65%), whereas none of the patients with stable or progressive disease showed a decrease of ;;.30%. Stable disease was noted in 16 patients. In 13 patients the CA 125 levels remained unchanged, whereas halving of the antigen level was observed in three patients. Relapse. CA 125 levels were elevated in 27 of 29 patients who developed relapse. All patients with previously elevated CA 125 levels showed increasing antigen levels at the time of relapse. CA 125 levels at second-look laparotomy. Secondlook laparotomy was performed in 21 patients (Table V). The tumor sizes associated with a normal CA 125 level in patients with previously elevated antigen values ranged frotn 5 to 20 mm. One patient, who was free of tumor at second-look laparotomy but had an elevated CA 125level, had an intraperitoneal relapse 16 months later. Comment
CA 125 is an antigen associated with a high molecular weight glycoprotein, which is expressed by more than 80% of nonmucihous ovarian carcinomas.'· 6 - 10 The specificity for ovarian carcinoma is poor, as the antigen is also associated with other carcinomas.'· 6 • 7 • 10 Conse-
Table V. CA 125 levels* and findings at second-look laparotomy Completeness of primary operation Antigen level
Second-look finding
CA 125 <35 U/ml CA 125 ;;.35 Ulml
Tumor No tumor Tumor No tumor
Total
Residual tumor
3 5t 1 1:j: 10
I
No residual tumor
0 11§ 0 0 11
*Samples were obtained in the week before second-look laparotomy. tThree patients had a relapse. :j:Relapse. §One patient had a relapse.
quently, serum CA 125 has not proved useful for differential diagnosis of carcinomas of unknown origin. CA 125 has been shown to be elevated in a number of benign conditions such as endometriosis, pregnancy, pelvic inflammatory disease, and liver cirrhosis/· 10• " precluding use of CA 125 estimation as a screening method for asymptomatic patients. However, CA 125 has been shown to be promising for monitoring patients with epithelial ovarian cancer.'· 6 -9 This study reveals an elevation of serum CA 125 levels in 86% of patients with ovarian cancer. This finding is consistent with earlier studies.'· 6 ' 9 Originally the usefulness of the test was restricted to nonmucinous epithelial tumors.' However, later reports and our findings suggest that all histologic types of ovarian cancers can be accompanied by elevated CA i25 levels6 • 8 • 9 (Table II). Although mucinous and clear cell carcinomas often show elevated CA 125 levels, the antigen levels were significantly lower than in serous cystadenocarcinomas. No difference was observed when serous carcinomas were compared with the other types of epithelial tumors. Furthermore, an inverse relationship between serum CA 125 levels and the degree of differentiation was observed (Table III). The higher CA 125 levels in less differentiated tumors were not caused by a difference in tumor burden, since no cor-
92
Vergote, B0rmer, and Abeler
relation was observed between the degree of differentiation and tumor burden (p = 0.4). A remarkably good correlation (90% to 93%) has been reported between disease evolution during chemotherapy and CA 125 levels.'· 6 "9 This correlation is confirmed in the current study (92%) (Table IV). However, no additional information would be obtained from this test if the data coincided with the clinical findings. It is therefore interesting to note that both in earlier studies and in the present report elevations of CA 125 preceded clinical detection of progression with a median of 3 months. 9 · 12 In the current series we observed that rising CA 125 levels were always associated with progressive disease and that 4 weeks after the first course of chemotherapy all responding patients exhibited a 30% to 95% decrease in the antigen levels, whereas none of the patients with stable or progressive disease showed a decrease of :;;.30%. Normalization of CA 125 3 months after the initiation of chemotherapy was observed only in patients with complete or partial response. These findings suggest that early identification of nonresponders, resulting in a reduction of toxicity by avoidance of ineffective therapy, is possible. Sevelda et al. 6 suggested that chemotherapy may select CA 125-negative cell clones. This phenomenon has also been observed with other tumor markers. 13 We observed no such tendency, as all patients with previously elevated CA 125levels showed rising values when developing a relapse after chemotherapy. Several studies' 2 • 14 " 16 have demonstrated that an elevated CA 125 level may predict the presence of intraperitoneal tumors at second-look procedures but that a normal CA 125 level does not exclude the presence of disease. These findings were confirmed in the present study; the maximum tumor size associated with a normal CA 125 level in patients with previously elevated antigen concentrations was 20 mm. One patient free of tumor at second-look laparotomy but with an elevated CA 125 level had an intraperitoneal relapse 16 months later. The prognostic value of preoperative and postoperative CA 125 levels has been evaluated in this study. The preoperative CA 125 levels tended to correlate inversely with survival in patients with Stage III or IV disease. In patients without residual tumor an elevated
July 1987 Am J Obstet Gynecol
CA 125 level (sampled 3 to 6 weeks after operation) was a bad prognostic index. REFERENCES I. Bast RC, Klug TL, St. John E, et al. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Eng! J Med 1983;309:883. 2. Pederson F, Kolstad P, Ludwig H, et al. Annual report on the results of treatment in gynecologic cancer. Stockholm: Radiumhemmet, 1985, vol 19:210-3. 3. Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer 1981;47:207. 4. Serov SF, Scully RE, Sobin LH. Histological typing of ovarian tumours. In: International histological classification of tumours. no. 9. Geneva: World Health Organization, 1973:17-8. 5. Goldstein A. Biostatistics: an introductory text. New York: Macmillan, 1964. 6. Sevelda P, Salzer H, Dittrich C, et al. Die klinische Bedeutung des Tumormarkers CA-125 fur die praeoperative Diagnostik und die postoperative N achbetreuung von Patientinnen mit malignen Ovarialtumoren. Geburtshilfe Frauenheilkd 1985;45:769. 7. Ricolleau G, ChatalJF, Fumoleau P, Kremer M, Douillard JY, Curtet C. Radioimmunoassay of the CAI25 antigen in ovarian carcinomas: advantages compared with ('.A19-9 and CEA. Tumour Bioi 1984;5:151. 8. Cariney PA, Moore M, Wilkinson PM, James RD. Ovarian cancer antigen CAI25: a prospective clinical assessment of its role as a tumour marker. Br J Cancer 1984;50:765. 9. Crombach G, Zippel H, Wurz H. Erfahrungen mitCAI25, einem Tumormarker fur maligne epitheliale Ovarialtumoren. Gerburtshilfe Frauenheilkd 1985;45:205. 10. Hallilla H, Stenman UH, Seppalla M. Ovarian cancer antigen CA 125 levels in pelvic inflammatory disease and pregnancy. Cancer 1986;57:1327. II. Barbieri RL, Niloff JM, Bast RC, Schaetzl E, Kistner RW, Knapp RC. Elevated serum concentrations of CA-125 in patients with advanced endometriosis. Fertil Steril 1986; 45:630. 12. Niloff JM, Knapp RC, Lavin PT, et al. TheCA 125 assay as a predictor of clinical recurrence in epithelial ovarian cancer. AM j 0BSTET GYNECOL 1986;155:56. 13. Vergote I, Onsrud M, Nustad K. Placental alkaline phosphatase as a tumor marker in ovarian cancer. Obstet Gynecol 1987;69:228. 14. Niloff JM, Bast RC, Schaetzl EM, Knapp RC. Predictive value of CAI25 antigen levels in second-look procedures. AM] 0BSTET GYNECOL 1985;151:981. 15. Atack DB, Nisker JA, Allen HH, Tustanoff ER, Levin L. CA 125 surveillance and second-look laparotomy in ovarian carcinoma. AMJ 0BSTET GYNECOL 1986;154:287. 16. BerekJS, Knapp RC, Malkasian GD, et al. CA 125levels correlate with second-look operations among ovarian cancer patients: a prospective multi-institutional study. Obstet Gynecol1986;67:685.
5. Sbarra AJ, Michlevitz H, Selvaraj RJ, et a!. Correlation between amniotic fluid optical density and LIS ratio. Obstet Gynecol 1976;48:613. 6. Touchstone JC, Levin SS, Dobbins MF, Matthews L, Beere PC, Gabbe SG. (3-sm-phosphatidyl) cholines (lecithins) in amniotic fluid. Clin Chern 1983;29:1951. 7. Gluck L, Kulovich MV, Borer RC, Brenner PH, Anderson GG, Spellacy WN. Diagnosis of the respiratory distress syndrome by amniocentesis. AM J 0BSTET GYNECOL 1971; 109:440. 8. Haney D, Parkinson CE, Campbell S. Risk of respiratory distress syndrome. Lancet 1975;1:42. 9. Herbert WNP, Tyson J, Jimenez JM. Severity of respiratory distress syndrome with low lecithin: sphingomyelin ratio. Obstet Gynecol 1981 ;57:426.
July 1987 Am J Obstet Gynecol
I 0. Gab be SG. Recent advances in the assessment of fetal lung maturity. J Reprod Med 1979;23:228. II. Garite TJ, Freeman RK, Nageotte MP. Fetal maturity cascade: a rapid and cost effective method for fetal lung maturity testing. Obstet Gynecol 1986;67:619. 12. Maniscalco WM, Finkelstein JN, Parkhurst AB. De novo fatty acid synthesis in developing lung. Biochim Biophys Acta 1982;7ll:49. 13. Groener JEM, Van Rozen AJ, Cibelens DW. Cholesteryl ester transfer activity: localization and role in distribution of cholesteryl ester among lipoproteins in man. Atherosclerosis 1984;50:261.
Evaluation of serum CA 125 levels in the monitoring of ovanan cancer Ignace B. Vergote, M.D.,* Ole P. Bf
Key words: CA 125 serum levels, monitoring, ovarian cancer The natural history of ovarian cancer is characterized by intra-abdominal spread, which hinders early diagnosis and accurate monitoring of the disease. During recent decades a large number of antigens have been detected in ovarian cancers. Bast et a!.' developed a promising assay based on a murine monoclonal antibody (OC 125), reacting with the antigen CA 125, which is expressed by more than 80% of nonmucinous epi-
From the Departments of Gynecologic Oncology and Pathology and the Central Laboratory of The Norwegian Radium Hospital. Received for publication October 3, 1986; revised january 8, 1987; accepted February 6, 1987. Reprint requests: Ignace B. Vergote, M.D., Department of Gynecologic Oncology, The Norwegian Radium Hospital, Montebello, N-0310, Oslo, Norway. *Fellow of the NATO Research Foundation and the Belgian Fund for Scientific Research.
88
thelia! ovarian cancers. The objectives of this study were to investigate the prognostic value of preoperative and postoperative CA 125 serum levels in ovarian cancer, to determine the value of CA 125 in monitoring the disease, and to assess the correlation between CA 125 serum levels and histologic type and degree of differentiation.
Material and methods A total of 606 serum samples from 227 patients with ovarian cancer have been tested for CA 125. The samples were obtained between February 1983 and February 1985 and stored at - 20° C until they were analyzed. All patients had follow-up until July 1986. The results of theCA 125 test were not known at the time of treatment. Clinical staging was performed according to the sys-
Volume 157 Number I
CA 125 in monitoring of ovarian cancer
89
Table I. Preoperative and postoperative CA 125 serum levels in ovarian cancer patients CA 125 level
Preoperative Postoperative* Without residual tumor <2 em Residual tumor ;;.2 em Residual tumor
n
>35 U/ml (n)
37
34
57 10 46
9 2 42
I
Median (Uiml) 439 1St 24t 187
I
Range (Uiml) 10-30800 2-203 6-1607 6-18400
*Samples were obtained 3 to 6 weeks after primary operation and before the start of chemotherapy. tp < 0.001 compared with the preoperative group and the postoperative group with ;;.2 em. of residual tumor.
terns adopted by the international Federation of Gynecology and Obstetrics.• This series included 71 patients in Stage I, 13 in Stage II, 108 in Stage III, and 35 in Stage IV disease. The principles of therapy consisted of primary operation followed by cytotoxic chemotherapy with cisplatin, cyclophosphamide, Thiotepa, or carboplatin or by instillation of radioactive phosphorus. Evaluation of response to treatment was based on clinical observations and radiologic data. Response to treatment was evaluated according to the recommendations of the World Health Organization.' Registration of disease progression requires a 25% or more increase in the size of the existing lesions or the appearance of a new lesion. Disease regression requires at least a 50% decrease in tumor size for at least 4 weeks for partial response and a disappearance of all clinical signs of malignancy for complete response. All relapses were confirmed by histologic or cytologic findings. One of the authors (V. M. A.) reviewed all the slides. The results of the CA 125 investigation were not known at that time. Histologic classification was performed with the criteria defined by the World Health Organization.< One hundred sixteen tumors were serous, 31 mucinous, 22 endometrioid, 12 clear cell, 12 undifferentiated, 18 mixed, and 19 unclassifiable carcinomas. One patient had a malignant Brenner tumor, and three had nonepithelial tumors. CA 125 assays. CA 125 was measured by an immunoradiometric ("sandwich") assay (Abbott CA 125 radioimmunoassay, Abbott Laboratories, North Chicago, Illinois), performed according to the instructions of the manufacturer. This kit uses antibody OC 125 bound to polystyrene beads and radiolabeled OC 125 to measure the amount of antigen bound from samples and standards during incubation. The interassay coefficient of variation was 6% with the control sera of the kit. The reference limit of 35 U/ml, as proposed by Bast et al., 1 was verified in a small reference population. This group consisted of 45 patients with benign diseases. Only one patient in this group had a slightly elevated value. In serial analysis a doubling or halving
of the CA 125 levels was considered a significant increase or decrease. Sampling. Serum samples were obtained at the moment of referral to The Norwegian Radium Hospital. Most patients are referred in the postoperative phase or when they develop a relapse. This explains why we were unable to study the CA 125 levels in all patients during the entire treatment period. Serum samples were available from 37 patients before staging laparotomy and from 113 patients after operation. Sampling was performed in the week before laparotomy in the former group and 3 to 6 weeks after operation and before the start of chemotherapy or radiotherapy in the latter group. The postoperative group consisted of 56 patients with residual disease and 57 patients without any. The group of patients with preoperative measurements was small because the majority of patients were referred to our hospital after primary operation. In 112 patients with epithelial cancer serial measurements were performed during chemotherapy. Thirteen cases were excluded ( 11 with initially normal CA 125 levels and two with nonepithelial tumors). Serum samples were assessable at the moment of relapse in 29 patients who previously had received chemotherapy but had been free of treatment for at least 3 months. Second-look laparotomy was performed in 21 patients without clinical or radiologic evidence of disease. Eleven patients were free of tumor after the primary operation. Serum samples were collected in the week before second-look operation. Statistical analysis. For statistical analysis the x• test and the Wilcoxon test were used. 5 When no statistical analysis is mentioned, the Wilcoxon test was used. Results
CA 125 levels in preoperative and postoperative patients. Table I summarizes the preoperative and postoperative serum CA 125 levels. Postoperative CA 125 levels were significantly lower in patients without residual tumor and in patients with <2 em of re-
90
Vergote, B0rmer, and Abeler
July 1987 Am J Obstet Gynecol
Table II. Serum CA 125 levels in ovarian cancer patients with evidence of disease* in relation to histologic type CA 125 level Histologic type Epithelial tumors Serous cystadenocarcinoma Mucinous cystadenocarcinoma Endometrioid carcinoma Clear cell carcinoma Mixed carcinoma Undifferentiated carcinoma U nclassifiable carcinoma Mixed mesodermal tumor Carcinosarcoma
n
>35 Ulml (n)
68 4 8 6 10 4 12 1 1
61 3 6 3 9 3 11 1 1
346 47t 308 46:j: 286 309 333 395 48
7-30800 15-157 6-1727 12-329 15-3316 10-1000 6-1607
98 (86%)
266
6-30800
114
Total
Median (Uiml)
I
I
Range (Uiml)
*Preoperative and postoperative patients with evidence of disease at the moment of sampling and patients with untreated relapse. Patients who had more than one sample assessable have the first sample included. tp = 0.02 compared with serous cystadenocarcinoma. :j:p = 0.015 compared with serous cystadenocarcinoma.
Table III. Serum CA 125 levels in ovarian cancer patients with evidence of disease* in relation to degree of differentiation CA 125 level Differentiation
n
>35 Ulml (n)
Borderline Grade 1 Grade 2 Grade 3
4 8 26 76
3 5 24 66
I
Median (Uiml) 57t 53:j: 242 387
J
Range (Uiml) 7-157 14-358 30-4278 6-30800
*Preoperative and postoperative patients with evidence of disease and patients with untreated relapse. tp = 0.027 compared with values for grade 2 and 3 lesions. :j:p = 0.007 compared with values for grade 2 and 3 lesions.
sidual disease compared with the two other groups (preoperative or postoperative with >2 em of residual disease; for each group p < 0.001). There was no significant difference between the latter two groups or between the former two groups (p = 0.15 and p = 0.57, respectively). In 34 of 3 7 patients preoperative CA 125 values were elevated. One patient with Stage I disease, 24 with Stage Ill, and nine with Stage IV had elevated CA 125 levels. Three patients with Stage III had values within the normal range (two serous and one undifferentiated carcinoma). The prognostic value of preoperative CA 125 levels was evaluated in 36 patients with Stage III or IV disease. The CA 125 levels tended to correlate inversely with survival (median follow-up 26 months; p = 0.06). The prognostic value of postoperative CA 125 levels (sampled 3 to 6 weeks after staging laparotomy) in patients without residual tumor was evaluated in 57 cases. A raised postoperative CA 125 serum level implied a
bad prognosis, since four of eight patients with elevated levels had relapse, whereas only five of 49 patients with normal levels had relapse (median follow-up 24 months; x2 , p < 0.02). Histologic type and differentiation. The relation between histologic type and serum CA 125 levels in patients with evidence of disease is shown in Table II. CA 125 levels were significantly higher in serous cystadenocarcinomas than in mucinous and clear cell carcinomas (p = 0.02 and p = 0.015, respectively), but no significant difference was observed when serous cystadenocarcinomas were compared with the other epithelial tumors. Grade 2 and 3 tumors showed higher CA 125 serum levels than borderline and grade 1 tumors (p = 0.027 and p = 0.007, respectively). There was no significant difference between the former two groups (Table III). CA 125 monitoring profiles during chemotherapy. Serial measurements were performed during chemotherapy in 112 patients with epithelial cancer. These
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CA 125 in monitoring of ovarian cancer
91
Table IV. Variation inCA 125 levels with disease status in response to chemotherapy Disease status Antigen level*
Complete response
Partial response
Stable disease
Progression
Decreased Remained unchanged Increased
16 0 0
28 0 0
3 13 0
2 3 36
Total
16
28
16
41
*Doubling or halving of CA 125 levels was considered a significant increase or dectease.
findings are presented in Table IV. CA 125 levels correlated with the clinical course in 93 of 10 I cases (92%). A rising CA 125 level was always associated with disease progression (n = 36). In 16 of these patients a significant increase in CA 125 was observed at least . 1 month before clinical evidence of progression ( 1 to 8 months, median 3 months). Despite obvious clinical progression, two patients had decreasing CA 125 values (one serous and one clear cell carcinoma). CA 125 values normalized in 14 of 16 patients with complete response. Twelve of the 14 patients had a relapse during the observation period. During partial remission, CA 125 values normalized in nine of 28 patients, whereas CA 125 levels remained elevated in all patients with stable or progressive disease. CA 125 measurements were performed 4 weeks after the first course of chemotherapy in 14 patients with partial or complete remission. All patients had a decrease in CA 125 levels ranging from 30% to 95% (mean 65%), whereas none of the patients with stable or progressive disease showed a decrease of ;;.30%. Stable disease was noted in 16 patients. In 13 patients the CA 125 levels remained unchanged, whereas halving of the antigen level was observed in three patients. Relapse. CA 125 levels were elevated in 27 of 29 patients who developed relapse. All patients with previously elevated CA 125 levels showed increasing antigen levels at the time of relapse. CA 125 levels at second-look laparotomy. Secondlook laparotomy was performed in 21 patients (Table V). The tumor sizes associated with a normal CA 125 level in patients with previously elevated antigen values ranged frotn 5 to 20 mm. One patient, who was free of tumor at second-look laparotomy but had an elevated CA 125level, had an intraperitoneal relapse 16 months later. Comment
CA 125 is an antigen associated with a high molecular weight glycoprotein, which is expressed by more than 80% of nonmucihous ovarian carcinomas.'· 6 - 10 The specificity for ovarian carcinoma is poor, as the antigen is also associated with other carcinomas.'· 6 • 7 • 10 Conse-
Table V. CA 125 levels* and findings at second-look laparotomy Completeness of primary operation Antigen level
Second-look finding
CA 125 <35 U/ml CA 125 ;;.35 Ulml
Tumor No tumor Tumor No tumor
Total
Residual tumor
3 5t 1 1:j: 10
I
No residual tumor
0 11§ 0 0 11
*Samples were obtained in the week before second-look laparotomy. tThree patients had a relapse. :j:Relapse. §One patient had a relapse.
quently, serum CA 125 has not proved useful for differential diagnosis of carcinomas of unknown origin. CA 125 has been shown to be elevated in a number of benign conditions such as endometriosis, pregnancy, pelvic inflammatory disease, and liver cirrhosis/· 10• " precluding use of CA 125 estimation as a screening method for asymptomatic patients. However, CA 125 has been shown to be promising for monitoring patients with epithelial ovarian cancer.'· 6 -9 This study reveals an elevation of serum CA 125 levels in 86% of patients with ovarian cancer. This finding is consistent with earlier studies.'· 6 ' 9 Originally the usefulness of the test was restricted to nonmucinous epithelial tumors.' However, later reports and our findings suggest that all histologic types of ovarian cancers can be accompanied by elevated CA i25 levels6 • 8 • 9 (Table II). Although mucinous and clear cell carcinomas often show elevated CA 125 levels, the antigen levels were significantly lower than in serous cystadenocarcinomas. No difference was observed when serous carcinomas were compared with the other types of epithelial tumors. Furthermore, an inverse relationship between serum CA 125 levels and the degree of differentiation was observed (Table III). The higher CA 125 levels in less differentiated tumors were not caused by a difference in tumor burden, since no cor-
92
Vergote, B0rmer, and Abeler
relation was observed between the degree of differentiation and tumor burden (p = 0.4). A remarkably good correlation (90% to 93%) has been reported between disease evolution during chemotherapy and CA 125 levels.'· 6 "9 This correlation is confirmed in the current study (92%) (Table IV). However, no additional information would be obtained from this test if the data coincided with the clinical findings. It is therefore interesting to note that both in earlier studies and in the present report elevations of CA 125 preceded clinical detection of progression with a median of 3 months. 9 · 12 In the current series we observed that rising CA 125 levels were always associated with progressive disease and that 4 weeks after the first course of chemotherapy all responding patients exhibited a 30% to 95% decrease in the antigen levels, whereas none of the patients with stable or progressive disease showed a decrease of :;;.30%. Normalization of CA 125 3 months after the initiation of chemotherapy was observed only in patients with complete or partial response. These findings suggest that early identification of nonresponders, resulting in a reduction of toxicity by avoidance of ineffective therapy, is possible. Sevelda et al. 6 suggested that chemotherapy may select CA 125-negative cell clones. This phenomenon has also been observed with other tumor markers. 13 We observed no such tendency, as all patients with previously elevated CA 125levels showed rising values when developing a relapse after chemotherapy. Several studies' 2 • 14 " 16 have demonstrated that an elevated CA 125 level may predict the presence of intraperitoneal tumors at second-look procedures but that a normal CA 125 level does not exclude the presence of disease. These findings were confirmed in the present study; the maximum tumor size associated with a normal CA 125 level in patients with previously elevated antigen concentrations was 20 mm. One patient free of tumor at second-look laparotomy but with an elevated CA 125 level had an intraperitoneal relapse 16 months later. The prognostic value of preoperative and postoperative CA 125 levels has been evaluated in this study. The preoperative CA 125 levels tended to correlate inversely with survival in patients with Stage III or IV disease. In patients without residual tumor an elevated
July 1987 Am J Obstet Gynecol
CA 125 level (sampled 3 to 6 weeks after operation) was a bad prognostic index. REFERENCES I. Bast RC, Klug TL, St. John E, et al. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Eng! J Med 1983;309:883. 2. Pederson F, Kolstad P, Ludwig H, et al. Annual report on the results of treatment in gynecologic cancer. Stockholm: Radiumhemmet, 1985, vol 19:210-3. 3. Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer 1981;47:207. 4. Serov SF, Scully RE, Sobin LH. Histological typing of ovarian tumours. In: International histological classification of tumours. no. 9. Geneva: World Health Organization, 1973:17-8. 5. Goldstein A. Biostatistics: an introductory text. New York: Macmillan, 1964. 6. Sevelda P, Salzer H, Dittrich C, et al. Die klinische Bedeutung des Tumormarkers CA-125 fur die praeoperative Diagnostik und die postoperative N achbetreuung von Patientinnen mit malignen Ovarialtumoren. Geburtshilfe Frauenheilkd 1985;45:769. 7. Ricolleau G, ChatalJF, Fumoleau P, Kremer M, Douillard JY, Curtet C. Radioimmunoassay of the CAI25 antigen in ovarian carcinomas: advantages compared with ('.A19-9 and CEA. Tumour Bioi 1984;5:151. 8. Cariney PA, Moore M, Wilkinson PM, James RD. Ovarian cancer antigen CAI25: a prospective clinical assessment of its role as a tumour marker. Br J Cancer 1984;50:765. 9. Crombach G, Zippel H, Wurz H. Erfahrungen mitCAI25, einem Tumormarker fur maligne epitheliale Ovarialtumoren. Gerburtshilfe Frauenheilkd 1985;45:205. 10. Hallilla H, Stenman UH, Seppalla M. Ovarian cancer antigen CA 125 levels in pelvic inflammatory disease and pregnancy. Cancer 1986;57:1327. II. Barbieri RL, Niloff JM, Bast RC, Schaetzl E, Kistner RW, Knapp RC. Elevated serum concentrations of CA-125 in patients with advanced endometriosis. Fertil Steril 1986; 45:630. 12. Niloff JM, Knapp RC, Lavin PT, et al. TheCA 125 assay as a predictor of clinical recurrence in epithelial ovarian cancer. AM j 0BSTET GYNECOL 1986;155:56. 13. Vergote I, Onsrud M, Nustad K. Placental alkaline phosphatase as a tumor marker in ovarian cancer. Obstet Gynecol 1987;69:228. 14. Niloff JM, Bast RC, Schaetzl EM, Knapp RC. Predictive value of CAI25 antigen levels in second-look procedures. AM] 0BSTET GYNECOL 1985;151:981. 15. Atack DB, Nisker JA, Allen HH, Tustanoff ER, Levin L. CA 125 surveillance and second-look laparotomy in ovarian carcinoma. AMJ 0BSTET GYNECOL 1986;154:287. 16. BerekJS, Knapp RC, Malkasian GD, et al. CA 125levels correlate with second-look operations among ovarian cancer patients: a prospective multi-institutional study. Obstet Gynecol1986;67:685.