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Ovarian cancer: The prognostic value of the serum half-life of CA125 during induction chemotherapy
GYNECOLOGIC
ONCOLOGY
30, 307-3 12 (1988)
Ovarian Cancer: The Prognostic Value of the Serum Half-Life of CA1 25 during Induction Chemotherapy M. E. L. VAN DER BURG,* F. B. LAMMns,t W. L. J. VAN PUTTEN,* AND G. STOTER* *Rotterdam Cancer Institute, Rotterdam, The Netherlands, and tAcademic Medical Center, Amsterdam, The Netherlands Received January 19, 1988 Eighty-five patients with epithelial ovarian cancer were studied to assess the prognostic value of the prechemotherapy serum concentration of CA125 and its half-life during induction therapy. The endpoints of the analysis were progression rate and time to progression. The prechemotherapy CA125 level had no prognostic value (P = 0.36) if the patients were stratified for tumor size. The half-life of CA125, however, was an independent prognostic variable (P = 0.01). Patients with a half-life of 20 days and more had a 3.2 times higher progression rate and a significantly shorter median time to progression of only 11 months, as compared to 43 months for patients with a half-life of less than 20 days. o 1988 Academic Press, Inc.
INTRODUCTION The role of the cancer antigen CA125 in relation to ovarian cancer has been studied extensively. Elevated levels have been demonstrated in 80% of patients [l-3]. Changes in serum levels correlate with tumor growth and regression in more than 85% of patients. A rising CA125 precedes clinical detection of progression in 55-90% of cases with a median of 3 months, ranging from 1 to 17 months [I ,4-71. However, a normal CA125 level (below 35 U/ml) does not exclude tumor. At second-look operation only about 50% of patients with a normal CA125 appear to have a pathologically confirmed complete response [4,8]. Consequently, normalization of CA125 does not eliminate the need for second-look surgery to determine further therapy. On the other hand, a rising CA125 is almost always associated with tumor progression and makes a second-look operation superfluous [1,4,91. Recently, some investigators have attempted to gain additional prognostic information by analyzing changes in CA125 levels in response to induction chemotherapy. In a small group of 15 patients, Canney et al. [9] found a difference in half-life of CA125 between patients with a response to therapy and patients with stable disease. Patients who achieved a response had a mean half-life of less than 9.2 days while patients with stable disease had a mean half-life of 22.6 307 0090~8258/88$1.50 Copyright 0 1988 by Academic Press, Inc. All rights of reproduction in any form reserved.
308
VAN
DER
BURG
ET AL.
days. Lavin et al. [lo] attempted to correlate the CA125 serum levels at 3 months after start of therapy with the response at second-look surgery. Nine of 14 patients with a normal CA125 level at 3 months had a complete response at second-look operation, whereas all 13 patients with a serum CA125 level of more than 35 U/ml had persistent tumor. If the half-life of CA125 would be a reliable prognostic indicator for progression rate and time to progression it would be a simple instrument to individualize treatment and diagnostic procedures. Prolonged halflife or a rising CA125 would indicate the need for an early change to salvage therapy if available, or to cessation of intensive chemotherapy of marginal benefit. We analyzed the hospital records of 98 patients to assess the prognostic value of the prechemotherapy CA125 level and its half-life during induction chemotherapy. PATIENTS AND METHODS Patients. In 98 consecutive patients with epithelial ovarian carcinoma referred to the Rotterdam Cancer Institute in the period of September 1979 to December 1983 and treated with combination chemotherapy, serial measurements of serum CA125 were performed. Thirteen patients were excluded: in seven patients no serum sample before the start of treatment was available and in six patients with an elevated CA125 level the interval between the pretreatment serum sample and the actual start of therapy was more than 18 days. Eighty-five patients were evaluable. Patient characteristics are shown in Table 1. Patients with FIG0 stage IIb, IIc, III, and IV were treated according to phase III protocols including Hexa-CAF versus CHAP-5 [l I], CHAP-5 versus CP [12], and a phase II study of CHAC-1 [13]. Patients with FIG0 stage I, IIa, and IIb without macroscopic residual tumor were treated with three courses of CHAP-l or CHAP-5 followed by radiotherapy of the whole abdomen with 20 Gy [14], or six courses of CHAP5 if incompletely staged. Serum samples. The serum samples were taken before each chemotherapy cycle. Since the cycle interval in the protocols varied from 3 to 5 weeks, the interval between the serum samples varied likewise. All samples were stored at -70°C and thawed just before the assay. CA125 was measured, using a commercially available kit (Centacor), according to manufacturer’s instructions. Serum half-life. Serum half-life (T&) was calculated according to the formula T& = dT/*log (CAI/CA2), in which CA1 is the CA125 value before the start of therapy, CA2 is the first normal CA125 value (below 35 U/ml) or the lowest CA125 value if CA125 did not normalize within 3 months after the start of therapy, dT is the interval in days between CA1 and CA2. For the determination of the FZ only patients with a CA1 of more than 60 U/ml taken within 18 days before the start of therapy and a second serum sample within 3 months after the start of therapy were included. Statistical methods. Cox proportional hazard model was used to analyze the relationship between the pretreatment CA125 level c.q. CA125 half-life (on a log scale) and progression rate. Both analyses were done with stratification for tumor size.
HALF-LIFE
309
OF CA125
TABLE 1 PATIENT CHARACTERISTICS
Number of patients FIG0 stage Stage I Stage II Stage III Stage IV Histology Endometrioid adenocarcinoma Serous cystadenocarcinoma Mutinous cystadenocarcinoma Adenocarcinoma Clear cell adenocarcinoma Histological grade Grade 1 Grade 2 Grade 3 Unknown Postoperative tumor size None or microscopic Less than 2 cm 2-5 cm 5-10 cm More than 10 cm Chemotherapy Hexa-Caf CHAP-5 CP CHAC-1 CHAP + radiotherapy
85 15 26 26 18 4 34 7 33
11 20 31 23 34 15 10 10 16
-
10 31 17 4 23
RESULTS Prechemorherapy
CA125 levels. Our analysis shows a significant difference in
progression rate between patients with residual tumor masses of less than 2 cm after operation and patients with larger tumor remnants. In these groups of patients we analyzed whether CA125 at the onset of chemotherapy was of additional prognostic value with regard to progression rate. Table 2 shows the relationship between the residual tumor mass, the pretreatment CA125 level, and the 3-year progression-free survival. Patients with tumor rests of more than 2 cm had a significantly higher progression rate (69%) than patients with tumor rests of less than 2 cm (33%). The prechemotherapy CA125 level shows the same strong correlation with progression rate for CA125 levels higher (61%) and lower (33%) than 35 U/ml. However, this difference disappears after stratification for tumor size (P = 0.36), since there is a strong association between tumor size and ZJ level. Half-life ofCAZ25. The half-life of CA125 could be calculated in 37 patients. Twenty-nine patients had a Zj between 8 and 40 days, 3 patients had a CA125 of 57, 63, and 70 days. In 5 patients CA125 was static or rising; in these patients
310
VAN DER BURG ET AL. TABLE 2 RESIDUAL
Tumor size
(cm) <2 cm
TUMOR MASS, THE PRECHEMOTHERAPY LEVEL OF PROGRESSION-FREE SURVIVAL
CA125
IN RELATION
TO ~-YEAR
PD (~3 years)
NED (3 years)
CA125
Total
W/ml)
(nr)
nr
%
nr
%
S35 35-60 >60
34 10 5 49 3 1 32 36
25 6 2 33 0 0 11 11
74 60 40 67% 34 31%
9 4 3 16 3 1 21 2s
26 40 60 33% 100 100 66 69%
Total S35 35-60 x50
>2 cm Total
the T4 was set at 100 days. The relationship between T$ and progression rate was analyzed with the Cox regression method stratifying for tumor size with log(G) as covariate. The analysis demonstrated a significantly positive correlation between T&and progression rate. The greatest difference in progression rate was found at a half-life of 20 days. The progression rate for patients with a half-life of 20 days or more was 3.2 times higher than for patients with a half-life of less than 20 days (P = 0.01). The time to progression was also significantly shorter in patients with a long half-life. Patients with a half-life of 20 days or more had a median time to progression of 11 months whereas patients with a half-life of less than 20 days had a median time to progression of 43 months (Fig. 1). DISCUSSION Treatment with cisplatin-combination chemotherapy has considerably improved response rate and progression-free survival in patients with advanced epithelial ovarian cancer [ 11,15]. Nevertheless, more than 50% of patients have progressive disease within 2 years. Better and probably more intensive therapies are needed
0
FIG.
12
24
36
48
60 MONTHS
1. Time to progression according to Ti of serum CA125.
HALF-LIFE
OF CA125
311
in order to improve the prognosis. Ideally new intensive treatment regimens should be evaluated in high-risk patients. In order to identify high-risk patients we have investigated the prognostic value of the prechemotherapy CA125 serum level and the half-life of serum CAl25. The prechemotherapy level of CA125 on itself is strongly correlated with progression rate and the probability of progression within 3 years. However, this correlation can be explained by the strong association between the size of the residual tumor mass and the prechemotherapy level of CA125. The half-life of CA125 appears to be significantly and independently correlated with progression rate and progression-free survival. The best discriminative value of half-life of CA125 to separate high-risk from low-risk patients was 20 days. The progression rate in patients with half-life of 20 days or more was 3.2 times higher than in patients with a half-life of less than 20 days. The median time to progression was 11 and 43 months for each category, respectively (Fig. 1). If these data can be confirmed in a prospective study of a larger group of patients we may have a method to distinguish accurately high-risk patients from low-risk patients as early as l-2 months after the start of chemotherapy. This creates the possibility to individualize the treatment strategies and assign highrisk patients to protocols with more intensive chemotherapy and low-risk patients to less intensive therapy, early in the course of treatment. ACKNOWLEDGMENTS We are indebted to J. Snoek-Liefrink, L. Groenendijk-Klootwijk, and I. Dijkstra for their support.
J. van Driel, A. Hoek-Hoek,
REFERENCES 1. Bast, R. C., Klug, T. L., John, E. S., Jenison, E., Niloff, J. M., Lazarus, H., Berkowitz, R. S., Leavitt, T., Gritliths, C. T., Parker, L., Zurawski, V. R., and Knapp, R. C. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer, N. Engl. J. Med. 309, 883-887 (1983). 2. Klug, T. L., Bast, R. C., Niloff, J. M., Knapp, R. C., and Zurawski, V. R. Monoclonal antibody immunoradiometric assay for an antigenic determinant (CA125) associated with human epithelial ovarian carcinomas, Cancer Res. 44, 1048-1053 (1984). 3. Bast, R. C., and Knapp, R. C. Humoral markers for epithelial ovarian carcinoma, in Ovarian malignancies, diagnostic and therapeutic advances (Clinical obstetrics and gynaecology) (M. S. Piver, Ed.), Livingstone, New York, pp. 11-25 (1987). 4. Niloff, J. M., Knapp, R. C., Lavin, P. T., Malkasian, G. D., Berek, J. S., Mortel, R., Whitney, C., Zurawski, V. R., and Bast, R. C. The CA125 assay as a predictor of clinical recurrence in epithelial ovarian cancer, Amer. J. Obstet, Gynecol. 155, 56-60 (1986). 5. Rodenburg, C. J., de Maaker, G. A., Trimbos, J. B. M. Z., Moolenaar, A. J., and van Oosterom, A. T. CA125 and TPA as markers in ovarian carcinoma, Neth. J. Med. 28, 536-540 (1985). 6. Sevelda, P., Salzer, H., Dittrich, C., and Spona, J. Die Klinische Bedeutung des Tumormarkers CA125 fiir die praoperative Diagnostik und die postoperative Nachbetreuung von Patientinnen mit malignen Ovarialtumoren, Geburfshilfe Frauenheika. 45, 769-773. (1985). 7. van der Burg, M. E. L., van Putten, W. L. J., and Cox, P. H. The monoclonal antibody CA125 as tumour marker in epithelial ovarian cancer in a longitudinal retrospective study. Proc. Amer. Sot. Clin. 116, C-450 (1985). 8. Berek, J. S., Knapp, R. C., Malkasian, G. D., Lavin, P. T., Whitney, C., Niloff, J. M., and Bast, R. C. CA125 serum levels correlated with second-look operations among ovarian cancer patients, Obstet. Gynecol. 67, 685-689 (1986).
312
VAN
DER
BURG
ET AL.
9. Canney, P. A., Moore, M., Wilkinson, P. M., and James, R. D. Ovarian Cancer Antigen CA125 A prospective clinical assessment of its role as a tumour marker, Brit J. Cancer 50, 765-769 (1984). 10. Lavin, P. T., Knapp, R. C., Malkasian, G., Whitney, C. W., Berek, J. C., and Bast, R. C. CA125 for the monitoring of ovarian carcinoma during primary therapy, Obstet. Gynecol. 69, 223-227 (1987). 11. Neijt, J. P., ten Bokkel Huinink, W. W., van der Burg, M. E. L., van Oosterom, A. T., Vriesendorp, R., Kooyman, C. D., van Lindert, A. C. M., Hamerlynck, J. V. T. H., van Lent, M., van Houwelingen, J. C., and Pinedo, H. M. Randomized trial comparing two combination chemotherapy regimens (Hexa-CAF v CHAP-5) in advanced ovarian carcinoma, Lancet ii, 594-600 (1984). 12. Neijt, J. P., ten Bokkel Huinink, W. W., van der Burg, M. E. L., van Oosterom, A. T., Willemse, P. H. B., Heintz, A. P. M., van Lent, M., Trimbos, J. B., Bouma, J., Vermorken, J. B., and van Houwelingen, J. C. Randomized trial comparing two combination chemotherapy regimens (CHAP-5 v CP) in advanced ovarian carcinoma, J. C/in. Oncol. 5, 1157-1168 (1987). 13. Ten Bokkel Huinink, W. W., van der Burg, M. E. L., van Oosterom, A. T., Vermorken, J. B., Veenhof, C., and Roosendaal, K. A pilot study of CHAC-I, Cancer Treat. Rev. 12, (Suppl. A), 77-82 (1985). 14. Van der Burg, M. E. L., van Oosterom, A. T., Neijt, J. P., Hoff, A. M., Kuipers, T., Tjho Heslinga, R. E., Warhun, C., and Subandono, A. J. Combination chemotherapy and radiotherapy in incompletely staged patients with ovarian carcinoma, Proc. 2nd Eur. Co& Clin. Oncol. 55, 5-40 (1983). 15. Sutton, G., Stehman, F. B., and Ehrlich, C. Chemotherapy of epithelial ovarian cancer, in Ovarian malignancies, diagnostic and therapeutic advances (Clinical obstetrics and gynaecology) (M. S. Piver, Ed.), Livingstone, New York, pp. 163-185 (1987).
ONCOLOGY
30, 307-3 12 (1988)
Ovarian Cancer: The Prognostic Value of the Serum Half-Life of CA1 25 during Induction Chemotherapy M. E. L. VAN DER BURG,* F. B. LAMMns,t W. L. J. VAN PUTTEN,* AND G. STOTER* *Rotterdam Cancer Institute, Rotterdam, The Netherlands, and tAcademic Medical Center, Amsterdam, The Netherlands Received January 19, 1988 Eighty-five patients with epithelial ovarian cancer were studied to assess the prognostic value of the prechemotherapy serum concentration of CA125 and its half-life during induction therapy. The endpoints of the analysis were progression rate and time to progression. The prechemotherapy CA125 level had no prognostic value (P = 0.36) if the patients were stratified for tumor size. The half-life of CA125, however, was an independent prognostic variable (P = 0.01). Patients with a half-life of 20 days and more had a 3.2 times higher progression rate and a significantly shorter median time to progression of only 11 months, as compared to 43 months for patients with a half-life of less than 20 days. o 1988 Academic Press, Inc.
INTRODUCTION The role of the cancer antigen CA125 in relation to ovarian cancer has been studied extensively. Elevated levels have been demonstrated in 80% of patients [l-3]. Changes in serum levels correlate with tumor growth and regression in more than 85% of patients. A rising CA125 precedes clinical detection of progression in 55-90% of cases with a median of 3 months, ranging from 1 to 17 months [I ,4-71. However, a normal CA125 level (below 35 U/ml) does not exclude tumor. At second-look operation only about 50% of patients with a normal CA125 appear to have a pathologically confirmed complete response [4,8]. Consequently, normalization of CA125 does not eliminate the need for second-look surgery to determine further therapy. On the other hand, a rising CA125 is almost always associated with tumor progression and makes a second-look operation superfluous [1,4,91. Recently, some investigators have attempted to gain additional prognostic information by analyzing changes in CA125 levels in response to induction chemotherapy. In a small group of 15 patients, Canney et al. [9] found a difference in half-life of CA125 between patients with a response to therapy and patients with stable disease. Patients who achieved a response had a mean half-life of less than 9.2 days while patients with stable disease had a mean half-life of 22.6 307 0090~8258/88$1.50 Copyright 0 1988 by Academic Press, Inc. All rights of reproduction in any form reserved.
308
VAN
DER
BURG
ET AL.
days. Lavin et al. [lo] attempted to correlate the CA125 serum levels at 3 months after start of therapy with the response at second-look surgery. Nine of 14 patients with a normal CA125 level at 3 months had a complete response at second-look operation, whereas all 13 patients with a serum CA125 level of more than 35 U/ml had persistent tumor. If the half-life of CA125 would be a reliable prognostic indicator for progression rate and time to progression it would be a simple instrument to individualize treatment and diagnostic procedures. Prolonged halflife or a rising CA125 would indicate the need for an early change to salvage therapy if available, or to cessation of intensive chemotherapy of marginal benefit. We analyzed the hospital records of 98 patients to assess the prognostic value of the prechemotherapy CA125 level and its half-life during induction chemotherapy. PATIENTS AND METHODS Patients. In 98 consecutive patients with epithelial ovarian carcinoma referred to the Rotterdam Cancer Institute in the period of September 1979 to December 1983 and treated with combination chemotherapy, serial measurements of serum CA125 were performed. Thirteen patients were excluded: in seven patients no serum sample before the start of treatment was available and in six patients with an elevated CA125 level the interval between the pretreatment serum sample and the actual start of therapy was more than 18 days. Eighty-five patients were evaluable. Patient characteristics are shown in Table 1. Patients with FIG0 stage IIb, IIc, III, and IV were treated according to phase III protocols including Hexa-CAF versus CHAP-5 [l I], CHAP-5 versus CP [12], and a phase II study of CHAC-1 [13]. Patients with FIG0 stage I, IIa, and IIb without macroscopic residual tumor were treated with three courses of CHAP-l or CHAP-5 followed by radiotherapy of the whole abdomen with 20 Gy [14], or six courses of CHAP5 if incompletely staged. Serum samples. The serum samples were taken before each chemotherapy cycle. Since the cycle interval in the protocols varied from 3 to 5 weeks, the interval between the serum samples varied likewise. All samples were stored at -70°C and thawed just before the assay. CA125 was measured, using a commercially available kit (Centacor), according to manufacturer’s instructions. Serum half-life. Serum half-life (T&) was calculated according to the formula T& = dT/*log (CAI/CA2), in which CA1 is the CA125 value before the start of therapy, CA2 is the first normal CA125 value (below 35 U/ml) or the lowest CA125 value if CA125 did not normalize within 3 months after the start of therapy, dT is the interval in days between CA1 and CA2. For the determination of the FZ only patients with a CA1 of more than 60 U/ml taken within 18 days before the start of therapy and a second serum sample within 3 months after the start of therapy were included. Statistical methods. Cox proportional hazard model was used to analyze the relationship between the pretreatment CA125 level c.q. CA125 half-life (on a log scale) and progression rate. Both analyses were done with stratification for tumor size.
HALF-LIFE
309
OF CA125
TABLE 1 PATIENT CHARACTERISTICS
Number of patients FIG0 stage Stage I Stage II Stage III Stage IV Histology Endometrioid adenocarcinoma Serous cystadenocarcinoma Mutinous cystadenocarcinoma Adenocarcinoma Clear cell adenocarcinoma Histological grade Grade 1 Grade 2 Grade 3 Unknown Postoperative tumor size None or microscopic Less than 2 cm 2-5 cm 5-10 cm More than 10 cm Chemotherapy Hexa-Caf CHAP-5 CP CHAC-1 CHAP + radiotherapy
85 15 26 26 18 4 34 7 33
11 20 31 23 34 15 10 10 16
-
10 31 17 4 23
RESULTS Prechemorherapy
CA125 levels. Our analysis shows a significant difference in
progression rate between patients with residual tumor masses of less than 2 cm after operation and patients with larger tumor remnants. In these groups of patients we analyzed whether CA125 at the onset of chemotherapy was of additional prognostic value with regard to progression rate. Table 2 shows the relationship between the residual tumor mass, the pretreatment CA125 level, and the 3-year progression-free survival. Patients with tumor rests of more than 2 cm had a significantly higher progression rate (69%) than patients with tumor rests of less than 2 cm (33%). The prechemotherapy CA125 level shows the same strong correlation with progression rate for CA125 levels higher (61%) and lower (33%) than 35 U/ml. However, this difference disappears after stratification for tumor size (P = 0.36), since there is a strong association between tumor size and ZJ level. Half-life ofCAZ25. The half-life of CA125 could be calculated in 37 patients. Twenty-nine patients had a Zj between 8 and 40 days, 3 patients had a CA125 of 57, 63, and 70 days. In 5 patients CA125 was static or rising; in these patients
310
VAN DER BURG ET AL. TABLE 2 RESIDUAL
Tumor size
(cm) <2 cm
TUMOR MASS, THE PRECHEMOTHERAPY LEVEL OF PROGRESSION-FREE SURVIVAL
CA125
IN RELATION
TO ~-YEAR
PD (~3 years)
NED (3 years)
CA125
Total
W/ml)
(nr)
nr
%
nr
%
S35 35-60 >60
34 10 5 49 3 1 32 36
25 6 2 33 0 0 11 11
74 60 40 67% 34 31%
9 4 3 16 3 1 21 2s
26 40 60 33% 100 100 66 69%
Total S35 35-60 x50
>2 cm Total
the T4 was set at 100 days. The relationship between T$ and progression rate was analyzed with the Cox regression method stratifying for tumor size with log(G) as covariate. The analysis demonstrated a significantly positive correlation between T&and progression rate. The greatest difference in progression rate was found at a half-life of 20 days. The progression rate for patients with a half-life of 20 days or more was 3.2 times higher than for patients with a half-life of less than 20 days (P = 0.01). The time to progression was also significantly shorter in patients with a long half-life. Patients with a half-life of 20 days or more had a median time to progression of 11 months whereas patients with a half-life of less than 20 days had a median time to progression of 43 months (Fig. 1). DISCUSSION Treatment with cisplatin-combination chemotherapy has considerably improved response rate and progression-free survival in patients with advanced epithelial ovarian cancer [ 11,15]. Nevertheless, more than 50% of patients have progressive disease within 2 years. Better and probably more intensive therapies are needed
0
FIG.
12
24
36
48
60 MONTHS
1. Time to progression according to Ti of serum CA125.
HALF-LIFE
OF CA125
311
in order to improve the prognosis. Ideally new intensive treatment regimens should be evaluated in high-risk patients. In order to identify high-risk patients we have investigated the prognostic value of the prechemotherapy CA125 serum level and the half-life of serum CAl25. The prechemotherapy level of CA125 on itself is strongly correlated with progression rate and the probability of progression within 3 years. However, this correlation can be explained by the strong association between the size of the residual tumor mass and the prechemotherapy level of CA125. The half-life of CA125 appears to be significantly and independently correlated with progression rate and progression-free survival. The best discriminative value of half-life of CA125 to separate high-risk from low-risk patients was 20 days. The progression rate in patients with half-life of 20 days or more was 3.2 times higher than in patients with a half-life of less than 20 days. The median time to progression was 11 and 43 months for each category, respectively (Fig. 1). If these data can be confirmed in a prospective study of a larger group of patients we may have a method to distinguish accurately high-risk patients from low-risk patients as early as l-2 months after the start of chemotherapy. This creates the possibility to individualize the treatment strategies and assign highrisk patients to protocols with more intensive chemotherapy and low-risk patients to less intensive therapy, early in the course of treatment. ACKNOWLEDGMENTS We are indebted to J. Snoek-Liefrink, L. Groenendijk-Klootwijk, and I. Dijkstra for their support.
J. van Driel, A. Hoek-Hoek,
REFERENCES 1. Bast, R. C., Klug, T. L., John, E. S., Jenison, E., Niloff, J. M., Lazarus, H., Berkowitz, R. S., Leavitt, T., Gritliths, C. T., Parker, L., Zurawski, V. R., and Knapp, R. C. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer, N. Engl. J. Med. 309, 883-887 (1983). 2. Klug, T. L., Bast, R. C., Niloff, J. M., Knapp, R. C., and Zurawski, V. R. Monoclonal antibody immunoradiometric assay for an antigenic determinant (CA125) associated with human epithelial ovarian carcinomas, Cancer Res. 44, 1048-1053 (1984). 3. Bast, R. C., and Knapp, R. C. Humoral markers for epithelial ovarian carcinoma, in Ovarian malignancies, diagnostic and therapeutic advances (Clinical obstetrics and gynaecology) (M. S. Piver, Ed.), Livingstone, New York, pp. 11-25 (1987). 4. Niloff, J. M., Knapp, R. C., Lavin, P. T., Malkasian, G. D., Berek, J. S., Mortel, R., Whitney, C., Zurawski, V. R., and Bast, R. C. The CA125 assay as a predictor of clinical recurrence in epithelial ovarian cancer, Amer. J. Obstet, Gynecol. 155, 56-60 (1986). 5. Rodenburg, C. J., de Maaker, G. A., Trimbos, J. B. M. Z., Moolenaar, A. J., and van Oosterom, A. T. CA125 and TPA as markers in ovarian carcinoma, Neth. J. Med. 28, 536-540 (1985). 6. Sevelda, P., Salzer, H., Dittrich, C., and Spona, J. Die Klinische Bedeutung des Tumormarkers CA125 fiir die praoperative Diagnostik und die postoperative Nachbetreuung von Patientinnen mit malignen Ovarialtumoren, Geburfshilfe Frauenheika. 45, 769-773. (1985). 7. van der Burg, M. E. L., van Putten, W. L. J., and Cox, P. H. The monoclonal antibody CA125 as tumour marker in epithelial ovarian cancer in a longitudinal retrospective study. Proc. Amer. Sot. Clin. 116, C-450 (1985). 8. Berek, J. S., Knapp, R. C., Malkasian, G. D., Lavin, P. T., Whitney, C., Niloff, J. M., and Bast, R. C. CA125 serum levels correlated with second-look operations among ovarian cancer patients, Obstet. Gynecol. 67, 685-689 (1986).
312
VAN
DER
BURG
ET AL.
9. Canney, P. A., Moore, M., Wilkinson, P. M., and James, R. D. Ovarian Cancer Antigen CA125 A prospective clinical assessment of its role as a tumour marker, Brit J. Cancer 50, 765-769 (1984). 10. Lavin, P. T., Knapp, R. C., Malkasian, G., Whitney, C. W., Berek, J. C., and Bast, R. C. CA125 for the monitoring of ovarian carcinoma during primary therapy, Obstet. Gynecol. 69, 223-227 (1987). 11. Neijt, J. P., ten Bokkel Huinink, W. W., van der Burg, M. E. L., van Oosterom, A. T., Vriesendorp, R., Kooyman, C. D., van Lindert, A. C. M., Hamerlynck, J. V. T. H., van Lent, M., van Houwelingen, J. C., and Pinedo, H. M. Randomized trial comparing two combination chemotherapy regimens (Hexa-CAF v CHAP-5) in advanced ovarian carcinoma, Lancet ii, 594-600 (1984). 12. Neijt, J. P., ten Bokkel Huinink, W. W., van der Burg, M. E. L., van Oosterom, A. T., Willemse, P. H. B., Heintz, A. P. M., van Lent, M., Trimbos, J. B., Bouma, J., Vermorken, J. B., and van Houwelingen, J. C. Randomized trial comparing two combination chemotherapy regimens (CHAP-5 v CP) in advanced ovarian carcinoma, J. C/in. Oncol. 5, 1157-1168 (1987). 13. Ten Bokkel Huinink, W. W., van der Burg, M. E. L., van Oosterom, A. T., Vermorken, J. B., Veenhof, C., and Roosendaal, K. A pilot study of CHAC-I, Cancer Treat. Rev. 12, (Suppl. A), 77-82 (1985). 14. Van der Burg, M. E. L., van Oosterom, A. T., Neijt, J. P., Hoff, A. M., Kuipers, T., Tjho Heslinga, R. E., Warhun, C., and Subandono, A. J. Combination chemotherapy and radiotherapy in incompletely staged patients with ovarian carcinoma, Proc. 2nd Eur. Co& Clin. Oncol. 55, 5-40 (1983). 15. Sutton, G., Stehman, F. B., and Ehrlich, C. Chemotherapy of epithelial ovarian cancer, in Ovarian malignancies, diagnostic and therapeutic advances (Clinical obstetrics and gynaecology) (M. S. Piver, Ed.), Livingstone, New York, pp. 163-185 (1987).