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The Ability of Preoperative Serum CA-125 to Predict Optimal Primary Tumor Cytoreduction in Stage III Epithelial Ovarian Carcinoma
Gynecologic Oncology 77, 227–231 (2000) doi:10.1006/gyno.2000.5749, available online at http://www.idealibrary.com on
The Ability of Preoperative Serum CA-125 to Predict Optimal Primary Tumor Cytoreduction in Stage III Epithelial Ovarian Carcinoma Dennis S. Chi, M.D.,* Ennapadam S. Venkatraman, Ph.D.,† Vivek Masson, M.D.,* and William J. Hoskins, M.D.* *Gynecology Service, Department of Surgery, and †Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan–Kettering Cancer Center, New York, New York 10021 Received October 8, 1999
Purpose. The aim of this study was to determine the ability of preoperative serum CA-125 to predict optimal primary tumor cytoreduction in patients with Stage III epithelial ovarian carcinoma. Methods. We performed a retrospective chart review of 100 consecutive patients with Stage III ovarian carcinoma who had a serum CA-125 drawn prior to primary cytoreductive surgery. We used a receiver operating characteristic curve to determine the CA-125 level with the maximal prognostic power in predicting optimal versus suboptimal cytoreduction. Results. The median CA-125 level for the 100 patients was 819 U/ml (range 5.6 –26,200 U/ml). Optimal cytoreduction (diameter of largest residual tumor nodule <1 cm) was obtained in 45 cases (45%). The probability of performing optimal cytoreduction decreased with increasing CA-125 levels. A preoperative CA-125 level of 500 U/ml was identified as the value with the most predictive power. Optimal cytoreduction was achieved in 33 of the 45 cases (73%) with a CA-125 less than 500 U/ml compared to only 12 of the 55 cases (22%) with a CA-125 greater than 500 U/ml. Using a threshold level of 500 U/ml, the preoperative serum CA-125 level was able to predict optimal versus suboptimal cytoreduction with a sensitivity of 78%, specificity of 73%, positive predictive value of 78%, and negative predictive value of 73%. Conclusion. The probability of performing optimal cytoreduction in patients with Stage III ovarian carcinoma and a preoperative CA-125 greater than 500 U/ml was approximately one in five. These patients may be candidates for initial laparoscopic evaluation to obtain a confirmatory tissue diagnosis and to determine resectability. © 2000 Academic Press
INTRODUCTION CA-125 is a glycoprotein antigen located on the surface of many epithelial ovarian cancers. It is often shed into the blood stream by the tumors. In 1983, Bast and colleagues [1] described the development of a radioimmunoassay that was able to detect CA-125 in the serum of patients with ovarian cancer. Since its introduction, the serum CA-125 assay has been evalPresented at the 30th Annual Meeting of the Society of Gynecologic Oncologists, San Francisco, CA, March 20 –24, 1999.
uated in the screening for ovarian cancer, as a tool to differentiate benign from malignant ovarian masses, and as an indicator of tumor status during and after chemotherapy [2– 6]. It has been reported that serum CA-125 is elevated (⬎35 U/ml) in 90% of advanced-stage epithelial ovarian cancers, while less than 50% of patients with Stage I disease have abnormal levels [7]. Therefore, it appears that perhaps a larger tumor burden leads to higher serum CA-125 levels. If the amount of serum CA-125 elevation depends on the tumor load and the ability to perform optimal tumor cytoreduction of advanced ovarian cancer is also a function of tumor bulk (along with other factors) [8], then the question arises, “is there a threshold serum CA-125 level above which optimal cytoreduction for patients with International Federation of Gynecology and Obstetrics (FIGO) Stage III ovarian cancer will probably not be achieved?” Since laparotomy with debulking that is suboptimal has not been shown to offer a survival advantage [9], this information could be used to modify the primary surgical approach or alter the standard sequence of cytoreductive surgery and chemotherapy [10 –12]. The purpose of this study is to determine the ability of the preoperative serum CA-125 level to predict optimal primary tumor cytoreduction in patients with Stage III epithelial ovarian carcinoma. METHODS The Virginia K. Pierce Gynecology Service Database at Memorial Sloan–Kettering Cancer Center was used to identify 100 consecutive patients with FIGO Stage III epithelial ovarian carcinoma who underwent primary cytoreductive surgery at our institution between January 1995 and December 1997. All 100 patients had a serum CA-125 level drawn preoperatively. Serum CA-125 was measured by a commercially available radioimmunoassay that remained the same throughout the study period. The primary surgeon in all cases was an attending gynecologic oncologist. Patients with ovarian carcinoma of low malignant potential were not included in this review. The patients’ individual records were reviewed and the
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following information abstracted: age at the time of surgery, preoperative CA-125 level, operative findings, operative procedure performed, residual disease at the completion of the procedure, and final histopathologic diagnosis. Optimal tumor cytoreduction was defined as being attained when the diameter of the largest residual tumor nodule remaining at the end of the procedure measured less than or equal to 1 cm. To determine the ability of the preoperative serum CA-125 level to predict optimal cytoreduction, the true-positive rate (sensitivity) was defined as the percentage of suboptimally cytoreduced patients who had a preoperative serum CA-125 level above various given cutoff values. The false-positive rate (one minus specificity) was defined as the percentage of optimally cytoreduced patients who had a preoperative serum CA-125 level above the given cutoff value. Receiver operating characteristic (ROC) curves methodology was then used to select the most clinically useful CA-125 threshold value [13, 14]. An ROC curve plots the true-positive rate along the y-axis and the false-positive rate along the x-axis for the various cutoff points. The area under the ROC curve is a measure of predictive accuracy where a value of 1 corresponds to a perfect predictor and 0.5 to a coin toss. Differences in the percentage of patients with tumor masses greater than 10 cm with serum CA-125 levels below and above 500 U/ml were compared using the Pearson 2 test [15]. RESULTS The median age of the 100 patients was 60 years (range 21– 83). Ninety-three patients (93%) had Stage IIIC disease, while 2 (2%) and 5 (5%) had Stage IIIA and IIIB disease, respectively. Seventy-eight patients (78%) had grade 3 tumors, while 3 (3%) and 19 (19%) had grade 1 and 2 tumors, respectively. Tumor histology was as follows: papillary serous 56 (56%); endometrioid 19 (19%); undifferentiated adenocarcinoma 12 (12%); clear-cell 8 (8%); and mixed 5 (5%). Using the definition of optimal cytoreduction as cases in which the diameter of the largest residual tumor nodule measured less than or equal to 1 cm, optimal tumor cytoreduction was obtained in 45 cases (45%). The remaining 15 patients (15%) left with 1- to 2-cm residual disease and the 40 patients (40%) with greater than 2-cm residual were defined as having had suboptimal cytoreduction. Six of the 7 patients (86%) with Stages IIIA and IIIB disease were optimally cytoreduced, whereas 39 of the 93 patients (42%) with Stage IIIC disease had optimal debulking. Optimal residual disease status was achieved in 1 of the 3 patients (33%) with grade 1 tumors, 12 of the 19 patients (63%) with grade 2 tumors, and 32 of the 78 patients (41%) with grade 3 tumors. The median serum CA-125 level for the 100 patients was 819 U/ml (range 5.6 –26,200 U/ml). The level was elevated (⬎35 U/ml) in 96 cases (96%). The probability of performing optimal cytoreduction decreased with increasing CA-125 levels. The true-positive and false-positive rates of various thresh-
TABLE 1 Prediction of Suboptimal Cytoreduction at Different Cutoff CA-125 Levels Cutoff CA-125 level (U/ml)
True-positive rate (sensitivity) (%)
False-positive rate (1-specificity) (%)
100 200 500 750 1000 2000 5000 10,000
96 91 78 75 66 27 9 5
85 67 27 24 22 4 2 0
old serum CA-125 levels for predicting suboptimal cytoreduction are shown in Table 1. Figure 1 shows the receiver operating characteristics curve generated by the data. The curve’s progression from the lower left-hand corner to the upper right-hand corner corresponds to successively lower cutoff CA-125 levels and a resultant increase in both the true-positive and the false-positive rates. The ideal test would have a true-positive rate of 100% with a false-positive rate of 0%, and it would be located at the left upper corner of the graph. The point on the curve closest to the left upper corner corresponds to a threshold serum CA-125 level of 500 U/ml and had an approximately equal number of false-positive and false-negative results. Forty-five patients (45%) had preoperative CA-125 levels below 500 U/ml, while the remaining 55 women (55%) had CA-125 levels above this value. Of the 45 patients with a CA-125 level ⬍500 U/ml, optimal cytoreduction was achieved in 33 (73%). However, optimal cytoreduction was attained in only 12 of the 55 cases (22%) with a preoperative CA-125 of greater than 500 U/ml (Table 2). Thus, at a threshold level of 500 U/ml, the preoperative serum CA-125 level was able to predict optimal versus suboptimal cytoreduction with a sensitivity of 78%, specificity of 73%, positive predictive value of 78%, and negative predictive value of 73%. We were unable to estimate initial total tumor volume in this retrospective review. However, the sizes of the largest tumor masses initially found at laparotomy were recorded. Seventyone patients (71%) were found to have tumor masses that measured greater than 10 cm in maximal dimension. Of these 71 patients, the largest mass was an ovarian tumor in 32 patients (45%), an omental cake in 24 cases (34%), and other abdominal tumor in 15 patients (21%). The presence of these large tumor masses did appear to correlate with the degree of preoperative serum CA-125 elevation. Of the 45 patients with CA-125 levels below 500 U/ml, 25 (56%) were found to have masses greater than 10 cm in diameter whereas 46 of the 55 women (84%) with levels above 500 U/ml had masses larger than 10 cm (P ⬍ 0.0036). Seven patients did not have large-volume upper abdominal
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FIG. 1. Receiver operating characteristic (ROC) curve showing the relationship between the true-positive rate (sensitivity) and false-positive rate (one minus specificity) using each serum CA-125 level as a cutoff point.
disease or positive lymph nodes and were designated as having Stage IIIA or IIIB disease. Six of these 7 patients (86%) were optimally cytoreduced, with 3 (43%) having serum CA-125 levels less than 500 U/ml. Of the 93 Stage IIIC patients, only 2 were assigned to this stage on the basis of lymph node metastasis without large-volume upper abdominal disease. Both patients had preoperative serum CA-125 levels less than 500 U/ml and grossly involved pelvic lymph nodes, which were completely resected at laparotomy. DISCUSSION Since the seminal work by Griffiths [16] in 1975, numerous retrospective studies have reported the benefits of tumor cyTABLE 2 Preoperative Serum CA-125 Level and Type of Cytoreduction (n ⴝ 100) CA-125 (U/ml)
No. pts optimal cytoreduction (%)
No. pts suboptimal cytoreduction (%)
⬍500 ⬎500 Total
33 (73) 12 (22) 45 (45)
12 (27) 43 (78) 55 (55)
toreduction for advanced ovarian carcinoma [17]. However, the Gynecologic Oncology Group (GOG) has demonstrated that tumor debulking improves overall survival only if optimal residual disease status can be attained [9]. Pooled data from reports from numerous institutions suggest that optimal primary cytoreduction can be achieved in approximately 30 to 40% of patients with advanced ovarian carcinoma [18]. Therefore, the traditional approach of laparotomy and attempted tumor cytoreduction does not significantly benefit the majority of patients with advanced disease. On the other hand, withholding attempts at cytoreduction may deprive a substantial number of patients from a procedure that could potentially double their median survival [18]. In an attempt to resolve this clinical dilemma and predict preoperatively which patients with ovarian cancer could be cytoreduced to optimal status (defined as ⱕ2 cm residual disease), Nelson and colleagues [19] retrospectively reviewed the preoperative computed tomography (CT) scans of 42 patients with various stages of ovarian cancer. Using CT scan criteria such as omental tumor attachment to the spleen and diaphragmatic lesions greater 2 cm, 12 of the 18 patients predicted to have suboptimal cytoreduction were in fact left with residual disease greater than 2 cm. This correlated to a
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positive predictive value of 67%. In this study, the addition of preoperative serum CA-125 levels did not enhance the accuracy of the CT scan in predicting cytoreducibility. Geisler et al. [20] evaluated preoperative serum CA-125 levels in 82 patients with various stages of ovarian carcinoma. The mean initial CA-125 level in patients who were able to be cytoreduced to less than 2 cm of residual disease was 966 U/ml, while those with greater than 2 cm of residual disease had a mean level of 3316 U/ml. These authors and others have suggested that the degree of elevation of CA-125 can probably be accounted for by the increased volume of disease, which consequently decreases the probability of attaining optimal cytoreduction. Although there is general consensus that optimal versus suboptimal surgical cytoreduction improves the prognosis for patients with advanced epithelial ovarian cancer, the most appropriate cutoff point has remained somewhat controversial. In the 1970s, the most common definition of optimal disease was that measuring less than or equal to 2 cm. In the early 1980s, the GOG defined optimal residual as that measuring ⬍3 cm in maximal diameter [21]. However, since 1986, the GOG has defined optimal residual disease as the diameter of the largest residual tumor nodule measuring ⱕ1 cm [9, 22]. We used the GOG definition of optimal cytoreduction in our series of 100 patients with Stage III ovarian carcinoma. The 45% optimal cytoreduction rate compares favorably with other reports in the literature, especially when one considers the high proportion of patients with Stage IIIC and grade 3 tumors, the use of less than or equal to 1 cm residual disease as the definition for optimal cytoreduction (compared to 1.5, 2.0, and 3.0 cm used in some other studies), and the referral nature of our institution. Nevertheless, the majority of patients were suboptimally cytoreduced and therefore did not sustain any long-term survival benefit from the procedure. The use of preoperative serum CA-125 levels may help to identify candidates for alternative approaches other than traditional laparotomy and attempted primary cytoreduction. Using a preoperative serum CA-125 level above 500 U/ml as a cutoff value to predict suboptimal cytoreduction, we identified 43 of the 55 patients who underwent suboptimal debulking (sensitivity of 78%). An alternative approach in the management of patients with CA-125 levels above 500 U/ml may be to perform initial laparoscopy to obtain a tissue diagnosis and evaluate for resectability. If the laparoscopy reveals disease amenable to optimal debulking, then standard laparotomy and attempted cytoreduction can be performed. However, if the findings are consistent with metastatic ovarian cancer that cannot be optimally cytoreduced, then neoadjuvant chemotherapy can be given almost immediately postoperatively. Subsequent laparotomy and cytoreduction can be performed after three or six cycles of neoadjuvant chemotherapy. Promising results have been reported with this approach of laparoscopic evaluation and neoadjuvant chemotherapy [11, 23]. The results of our study need confirmation in larger, perhaps
prospective, studies. With further study, we may find that different institutions with varied levels of surgical aggressiveness and optimal cytoreduction rates will have different threshold serum CA-125 levels for predicting optimal cytoreduction. However, if either uniform or institution-specific levels can be determined, we may be able to identify candidates for alternative approaches other than traditional laparotomy and attempted primary cytoreduction. REFERENCES 1. Bast RC Jr, Klug TL, St John E, Jenison E, Niloff JM, Lazarus H, Berkowitz RS, Leavitt T, Griffiths CT, Parker L, Zurawski VR Jr, Knapp RC: A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 309:883– 887, 1983 2. Zurawski VR Jr, Orjaseter H, Andersen A, Jellum E: Elevated serum CA 125 levels prior to diagnosis of ovarian neoplasia: relevance for early detection of ovarian cancer. Int J Cancer 42:677– 680, 1988 3. Vasilev SA, Schlaerth JB, Campeau J, Morrow CP: Serum CA-125 levels in preoperative evaluation of pelvic masses. Obstet Gynecol 71:751–756, 1988 4. Bridgewater JA, Nelstrop AE, Rustin GJ, Gore ME, McGuire WP, Hoskins WJ: Comparison of standard and CA-125 response criteria in patients with epithelial ovarian cancer treated with platinum or paclitaxel. J Clin Oncol 17:501–508, 1999 5. Rubin SC, Hoskins WJ, Hakes TB, Markman M, Reichman BS, Chapman D, Lewis JL Jr: Serum CA 125 levels and surgical findings in patients undergoing secondary operations for epithelial ovarian cancer. Am J Obstet Gynecol 160:667– 671, 1989 6. Bridgewater JA, Nelstrop AE, Rustin GJS, Gore ME, McGuire WP, Hoskins WJ: Comparison of standard and CA-125 response criteria in patients with epithelial ovarian cancer treated with platinum or paclitaxel. J Clin Oncol 17:501–508, 1999 7. Jacobs I, Bast RC Jr: The CA 125 tumour-associated antigen: a review of the literature. 8. Hoskins WJ, Bundy BN, Thigpen JT, Omura GA: The influence of cytoreductive surgery on recurrence-free interval and survival in smallvolume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 47:159 –166, 1992 9. Hoskins WJ, McGuire WP, Brady MF, Homesley HD, Creasman WT, Berman M, Ball H, Berek JS: The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol 170:974 –980, 1994 10. van der Burg ME, van Lent M, Buyse M, Kobierska A, Colombo N, Favalli G, Lacave AJ, Nardi M, Renard J, Pecorelli S: The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med 332:629 – 634, 1995 11. Vergote I, De Wever I, Tjalma W, Van Gramberen M, Decloedt J, van Dam P: Neoadjuvant chemotherapy or primary debulking surgery in advanced ovarian carcinoma: a retrospective analysis of 285 patients. Gynecol Oncol 71:431– 436, 1998 12. Schwartz PE, Rutherford TJ, Chambers JT, Kohorn EI, Thiel RP: Neoadjuvant chemotherapy for advanced ovarian cancer: long-term survival. Gynecol Oncol 72:93–99,1999 13. Peipert JF, Sweeney PJ: Diagnostic testing in obstetrics and gynecology: a clinician’s guide. Obstet Gynecol 82:619 – 623, 1993
SERUM CA-125 AND OVARIAN CANCER CYTOREDUCTION 14. Boardman LA, Peipert JF: Screening and diagnostic testing. Clin Obstet Gynecol 41:267–274, 1998 15. Zar JH: Biostatistical Analysis, Englewood Cliffs, NJ, Prentice Hall, 1974 16. Griffiths CT: Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr 42:101–104, 1975 17. Hoskins WJ: Epithelial ovarian carcinoma: principles of primary surgery. Gynecol Oncol 55:S91–S96, 1994 18. Ozols RF, Rubin SC, Thomas G, Robboy S: Epithelial Ovarian Cancer, in Hoskins WJ, Perez CA, Young RC (eds): Principles and Practice of Gynecologic Oncology, Second ed. Philadelphia, Lippincott-Raven, 1997, pp 919 –986 19. Nelson BE, Rosenfeld AT, Schwartz PE: Preoperative abdominopelvic computed tomographic prediction of optimal cytoreduction in epithelial ovarian carcinoma. J Clin Oncol 11:166 –172, 1993
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20. Geisler JP, Miller GA, Lee TH, Harwood RM, Wiemann MC, Geisler HE: Relationship of preoperative serum CA-125 to survival in epithelial ovarian carcinoma. J Reprod Med 41:140 –142, 1996 21. Omura GA, Blessing JA, Ehrlich CE, Miller A, Yordan E, Creasman WT, Homesley H: A randomized trial of cyclophosphamide and doxorubicin with or without cisplatin in advanced ovarian carcinoma. A Gynecologic Oncology Group study. Cancer 57:1725–1730, 1986 22. McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, Clarke-Pearson DL, Davidson M: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1– 6, 1996 23. Surwit EA, Childers JM, Alberts DS: Survival and morbidity of neoadjuvant chemotherapy compared to primary cytoreductive surgery in advanced ovarian cancer. Gynecol Oncol 68:122–123, 1998 (abstract 205)
The Ability of Preoperative Serum CA-125 to Predict Optimal Primary Tumor Cytoreduction in Stage III Epithelial Ovarian Carcinoma Dennis S. Chi, M.D.,* Ennapadam S. Venkatraman, Ph.D.,† Vivek Masson, M.D.,* and William J. Hoskins, M.D.* *Gynecology Service, Department of Surgery, and †Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan–Kettering Cancer Center, New York, New York 10021 Received October 8, 1999
Purpose. The aim of this study was to determine the ability of preoperative serum CA-125 to predict optimal primary tumor cytoreduction in patients with Stage III epithelial ovarian carcinoma. Methods. We performed a retrospective chart review of 100 consecutive patients with Stage III ovarian carcinoma who had a serum CA-125 drawn prior to primary cytoreductive surgery. We used a receiver operating characteristic curve to determine the CA-125 level with the maximal prognostic power in predicting optimal versus suboptimal cytoreduction. Results. The median CA-125 level for the 100 patients was 819 U/ml (range 5.6 –26,200 U/ml). Optimal cytoreduction (diameter of largest residual tumor nodule <1 cm) was obtained in 45 cases (45%). The probability of performing optimal cytoreduction decreased with increasing CA-125 levels. A preoperative CA-125 level of 500 U/ml was identified as the value with the most predictive power. Optimal cytoreduction was achieved in 33 of the 45 cases (73%) with a CA-125 less than 500 U/ml compared to only 12 of the 55 cases (22%) with a CA-125 greater than 500 U/ml. Using a threshold level of 500 U/ml, the preoperative serum CA-125 level was able to predict optimal versus suboptimal cytoreduction with a sensitivity of 78%, specificity of 73%, positive predictive value of 78%, and negative predictive value of 73%. Conclusion. The probability of performing optimal cytoreduction in patients with Stage III ovarian carcinoma and a preoperative CA-125 greater than 500 U/ml was approximately one in five. These patients may be candidates for initial laparoscopic evaluation to obtain a confirmatory tissue diagnosis and to determine resectability. © 2000 Academic Press
INTRODUCTION CA-125 is a glycoprotein antigen located on the surface of many epithelial ovarian cancers. It is often shed into the blood stream by the tumors. In 1983, Bast and colleagues [1] described the development of a radioimmunoassay that was able to detect CA-125 in the serum of patients with ovarian cancer. Since its introduction, the serum CA-125 assay has been evalPresented at the 30th Annual Meeting of the Society of Gynecologic Oncologists, San Francisco, CA, March 20 –24, 1999.
uated in the screening for ovarian cancer, as a tool to differentiate benign from malignant ovarian masses, and as an indicator of tumor status during and after chemotherapy [2– 6]. It has been reported that serum CA-125 is elevated (⬎35 U/ml) in 90% of advanced-stage epithelial ovarian cancers, while less than 50% of patients with Stage I disease have abnormal levels [7]. Therefore, it appears that perhaps a larger tumor burden leads to higher serum CA-125 levels. If the amount of serum CA-125 elevation depends on the tumor load and the ability to perform optimal tumor cytoreduction of advanced ovarian cancer is also a function of tumor bulk (along with other factors) [8], then the question arises, “is there a threshold serum CA-125 level above which optimal cytoreduction for patients with International Federation of Gynecology and Obstetrics (FIGO) Stage III ovarian cancer will probably not be achieved?” Since laparotomy with debulking that is suboptimal has not been shown to offer a survival advantage [9], this information could be used to modify the primary surgical approach or alter the standard sequence of cytoreductive surgery and chemotherapy [10 –12]. The purpose of this study is to determine the ability of the preoperative serum CA-125 level to predict optimal primary tumor cytoreduction in patients with Stage III epithelial ovarian carcinoma. METHODS The Virginia K. Pierce Gynecology Service Database at Memorial Sloan–Kettering Cancer Center was used to identify 100 consecutive patients with FIGO Stage III epithelial ovarian carcinoma who underwent primary cytoreductive surgery at our institution between January 1995 and December 1997. All 100 patients had a serum CA-125 level drawn preoperatively. Serum CA-125 was measured by a commercially available radioimmunoassay that remained the same throughout the study period. The primary surgeon in all cases was an attending gynecologic oncologist. Patients with ovarian carcinoma of low malignant potential were not included in this review. The patients’ individual records were reviewed and the
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0090-8258/00 $35.00 Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
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following information abstracted: age at the time of surgery, preoperative CA-125 level, operative findings, operative procedure performed, residual disease at the completion of the procedure, and final histopathologic diagnosis. Optimal tumor cytoreduction was defined as being attained when the diameter of the largest residual tumor nodule remaining at the end of the procedure measured less than or equal to 1 cm. To determine the ability of the preoperative serum CA-125 level to predict optimal cytoreduction, the true-positive rate (sensitivity) was defined as the percentage of suboptimally cytoreduced patients who had a preoperative serum CA-125 level above various given cutoff values. The false-positive rate (one minus specificity) was defined as the percentage of optimally cytoreduced patients who had a preoperative serum CA-125 level above the given cutoff value. Receiver operating characteristic (ROC) curves methodology was then used to select the most clinically useful CA-125 threshold value [13, 14]. An ROC curve plots the true-positive rate along the y-axis and the false-positive rate along the x-axis for the various cutoff points. The area under the ROC curve is a measure of predictive accuracy where a value of 1 corresponds to a perfect predictor and 0.5 to a coin toss. Differences in the percentage of patients with tumor masses greater than 10 cm with serum CA-125 levels below and above 500 U/ml were compared using the Pearson 2 test [15]. RESULTS The median age of the 100 patients was 60 years (range 21– 83). Ninety-three patients (93%) had Stage IIIC disease, while 2 (2%) and 5 (5%) had Stage IIIA and IIIB disease, respectively. Seventy-eight patients (78%) had grade 3 tumors, while 3 (3%) and 19 (19%) had grade 1 and 2 tumors, respectively. Tumor histology was as follows: papillary serous 56 (56%); endometrioid 19 (19%); undifferentiated adenocarcinoma 12 (12%); clear-cell 8 (8%); and mixed 5 (5%). Using the definition of optimal cytoreduction as cases in which the diameter of the largest residual tumor nodule measured less than or equal to 1 cm, optimal tumor cytoreduction was obtained in 45 cases (45%). The remaining 15 patients (15%) left with 1- to 2-cm residual disease and the 40 patients (40%) with greater than 2-cm residual were defined as having had suboptimal cytoreduction. Six of the 7 patients (86%) with Stages IIIA and IIIB disease were optimally cytoreduced, whereas 39 of the 93 patients (42%) with Stage IIIC disease had optimal debulking. Optimal residual disease status was achieved in 1 of the 3 patients (33%) with grade 1 tumors, 12 of the 19 patients (63%) with grade 2 tumors, and 32 of the 78 patients (41%) with grade 3 tumors. The median serum CA-125 level for the 100 patients was 819 U/ml (range 5.6 –26,200 U/ml). The level was elevated (⬎35 U/ml) in 96 cases (96%). The probability of performing optimal cytoreduction decreased with increasing CA-125 levels. The true-positive and false-positive rates of various thresh-
TABLE 1 Prediction of Suboptimal Cytoreduction at Different Cutoff CA-125 Levels Cutoff CA-125 level (U/ml)
True-positive rate (sensitivity) (%)
False-positive rate (1-specificity) (%)
100 200 500 750 1000 2000 5000 10,000
96 91 78 75 66 27 9 5
85 67 27 24 22 4 2 0
old serum CA-125 levels for predicting suboptimal cytoreduction are shown in Table 1. Figure 1 shows the receiver operating characteristics curve generated by the data. The curve’s progression from the lower left-hand corner to the upper right-hand corner corresponds to successively lower cutoff CA-125 levels and a resultant increase in both the true-positive and the false-positive rates. The ideal test would have a true-positive rate of 100% with a false-positive rate of 0%, and it would be located at the left upper corner of the graph. The point on the curve closest to the left upper corner corresponds to a threshold serum CA-125 level of 500 U/ml and had an approximately equal number of false-positive and false-negative results. Forty-five patients (45%) had preoperative CA-125 levels below 500 U/ml, while the remaining 55 women (55%) had CA-125 levels above this value. Of the 45 patients with a CA-125 level ⬍500 U/ml, optimal cytoreduction was achieved in 33 (73%). However, optimal cytoreduction was attained in only 12 of the 55 cases (22%) with a preoperative CA-125 of greater than 500 U/ml (Table 2). Thus, at a threshold level of 500 U/ml, the preoperative serum CA-125 level was able to predict optimal versus suboptimal cytoreduction with a sensitivity of 78%, specificity of 73%, positive predictive value of 78%, and negative predictive value of 73%. We were unable to estimate initial total tumor volume in this retrospective review. However, the sizes of the largest tumor masses initially found at laparotomy were recorded. Seventyone patients (71%) were found to have tumor masses that measured greater than 10 cm in maximal dimension. Of these 71 patients, the largest mass was an ovarian tumor in 32 patients (45%), an omental cake in 24 cases (34%), and other abdominal tumor in 15 patients (21%). The presence of these large tumor masses did appear to correlate with the degree of preoperative serum CA-125 elevation. Of the 45 patients with CA-125 levels below 500 U/ml, 25 (56%) were found to have masses greater than 10 cm in diameter whereas 46 of the 55 women (84%) with levels above 500 U/ml had masses larger than 10 cm (P ⬍ 0.0036). Seven patients did not have large-volume upper abdominal
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FIG. 1. Receiver operating characteristic (ROC) curve showing the relationship between the true-positive rate (sensitivity) and false-positive rate (one minus specificity) using each serum CA-125 level as a cutoff point.
disease or positive lymph nodes and were designated as having Stage IIIA or IIIB disease. Six of these 7 patients (86%) were optimally cytoreduced, with 3 (43%) having serum CA-125 levels less than 500 U/ml. Of the 93 Stage IIIC patients, only 2 were assigned to this stage on the basis of lymph node metastasis without large-volume upper abdominal disease. Both patients had preoperative serum CA-125 levels less than 500 U/ml and grossly involved pelvic lymph nodes, which were completely resected at laparotomy. DISCUSSION Since the seminal work by Griffiths [16] in 1975, numerous retrospective studies have reported the benefits of tumor cyTABLE 2 Preoperative Serum CA-125 Level and Type of Cytoreduction (n ⴝ 100) CA-125 (U/ml)
No. pts optimal cytoreduction (%)
No. pts suboptimal cytoreduction (%)
⬍500 ⬎500 Total
33 (73) 12 (22) 45 (45)
12 (27) 43 (78) 55 (55)
toreduction for advanced ovarian carcinoma [17]. However, the Gynecologic Oncology Group (GOG) has demonstrated that tumor debulking improves overall survival only if optimal residual disease status can be attained [9]. Pooled data from reports from numerous institutions suggest that optimal primary cytoreduction can be achieved in approximately 30 to 40% of patients with advanced ovarian carcinoma [18]. Therefore, the traditional approach of laparotomy and attempted tumor cytoreduction does not significantly benefit the majority of patients with advanced disease. On the other hand, withholding attempts at cytoreduction may deprive a substantial number of patients from a procedure that could potentially double their median survival [18]. In an attempt to resolve this clinical dilemma and predict preoperatively which patients with ovarian cancer could be cytoreduced to optimal status (defined as ⱕ2 cm residual disease), Nelson and colleagues [19] retrospectively reviewed the preoperative computed tomography (CT) scans of 42 patients with various stages of ovarian cancer. Using CT scan criteria such as omental tumor attachment to the spleen and diaphragmatic lesions greater 2 cm, 12 of the 18 patients predicted to have suboptimal cytoreduction were in fact left with residual disease greater than 2 cm. This correlated to a
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positive predictive value of 67%. In this study, the addition of preoperative serum CA-125 levels did not enhance the accuracy of the CT scan in predicting cytoreducibility. Geisler et al. [20] evaluated preoperative serum CA-125 levels in 82 patients with various stages of ovarian carcinoma. The mean initial CA-125 level in patients who were able to be cytoreduced to less than 2 cm of residual disease was 966 U/ml, while those with greater than 2 cm of residual disease had a mean level of 3316 U/ml. These authors and others have suggested that the degree of elevation of CA-125 can probably be accounted for by the increased volume of disease, which consequently decreases the probability of attaining optimal cytoreduction. Although there is general consensus that optimal versus suboptimal surgical cytoreduction improves the prognosis for patients with advanced epithelial ovarian cancer, the most appropriate cutoff point has remained somewhat controversial. In the 1970s, the most common definition of optimal disease was that measuring less than or equal to 2 cm. In the early 1980s, the GOG defined optimal residual as that measuring ⬍3 cm in maximal diameter [21]. However, since 1986, the GOG has defined optimal residual disease as the diameter of the largest residual tumor nodule measuring ⱕ1 cm [9, 22]. We used the GOG definition of optimal cytoreduction in our series of 100 patients with Stage III ovarian carcinoma. The 45% optimal cytoreduction rate compares favorably with other reports in the literature, especially when one considers the high proportion of patients with Stage IIIC and grade 3 tumors, the use of less than or equal to 1 cm residual disease as the definition for optimal cytoreduction (compared to 1.5, 2.0, and 3.0 cm used in some other studies), and the referral nature of our institution. Nevertheless, the majority of patients were suboptimally cytoreduced and therefore did not sustain any long-term survival benefit from the procedure. The use of preoperative serum CA-125 levels may help to identify candidates for alternative approaches other than traditional laparotomy and attempted primary cytoreduction. Using a preoperative serum CA-125 level above 500 U/ml as a cutoff value to predict suboptimal cytoreduction, we identified 43 of the 55 patients who underwent suboptimal debulking (sensitivity of 78%). An alternative approach in the management of patients with CA-125 levels above 500 U/ml may be to perform initial laparoscopy to obtain a tissue diagnosis and evaluate for resectability. If the laparoscopy reveals disease amenable to optimal debulking, then standard laparotomy and attempted cytoreduction can be performed. However, if the findings are consistent with metastatic ovarian cancer that cannot be optimally cytoreduced, then neoadjuvant chemotherapy can be given almost immediately postoperatively. Subsequent laparotomy and cytoreduction can be performed after three or six cycles of neoadjuvant chemotherapy. Promising results have been reported with this approach of laparoscopic evaluation and neoadjuvant chemotherapy [11, 23]. The results of our study need confirmation in larger, perhaps
prospective, studies. With further study, we may find that different institutions with varied levels of surgical aggressiveness and optimal cytoreduction rates will have different threshold serum CA-125 levels for predicting optimal cytoreduction. However, if either uniform or institution-specific levels can be determined, we may be able to identify candidates for alternative approaches other than traditional laparotomy and attempted primary cytoreduction. REFERENCES 1. Bast RC Jr, Klug TL, St John E, Jenison E, Niloff JM, Lazarus H, Berkowitz RS, Leavitt T, Griffiths CT, Parker L, Zurawski VR Jr, Knapp RC: A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 309:883– 887, 1983 2. Zurawski VR Jr, Orjaseter H, Andersen A, Jellum E: Elevated serum CA 125 levels prior to diagnosis of ovarian neoplasia: relevance for early detection of ovarian cancer. Int J Cancer 42:677– 680, 1988 3. Vasilev SA, Schlaerth JB, Campeau J, Morrow CP: Serum CA-125 levels in preoperative evaluation of pelvic masses. Obstet Gynecol 71:751–756, 1988 4. Bridgewater JA, Nelstrop AE, Rustin GJ, Gore ME, McGuire WP, Hoskins WJ: Comparison of standard and CA-125 response criteria in patients with epithelial ovarian cancer treated with platinum or paclitaxel. J Clin Oncol 17:501–508, 1999 5. Rubin SC, Hoskins WJ, Hakes TB, Markman M, Reichman BS, Chapman D, Lewis JL Jr: Serum CA 125 levels and surgical findings in patients undergoing secondary operations for epithelial ovarian cancer. Am J Obstet Gynecol 160:667– 671, 1989 6. Bridgewater JA, Nelstrop AE, Rustin GJS, Gore ME, McGuire WP, Hoskins WJ: Comparison of standard and CA-125 response criteria in patients with epithelial ovarian cancer treated with platinum or paclitaxel. J Clin Oncol 17:501–508, 1999 7. Jacobs I, Bast RC Jr: The CA 125 tumour-associated antigen: a review of the literature. 8. Hoskins WJ, Bundy BN, Thigpen JT, Omura GA: The influence of cytoreductive surgery on recurrence-free interval and survival in smallvolume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 47:159 –166, 1992 9. Hoskins WJ, McGuire WP, Brady MF, Homesley HD, Creasman WT, Berman M, Ball H, Berek JS: The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol 170:974 –980, 1994 10. van der Burg ME, van Lent M, Buyse M, Kobierska A, Colombo N, Favalli G, Lacave AJ, Nardi M, Renard J, Pecorelli S: The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med 332:629 – 634, 1995 11. Vergote I, De Wever I, Tjalma W, Van Gramberen M, Decloedt J, van Dam P: Neoadjuvant chemotherapy or primary debulking surgery in advanced ovarian carcinoma: a retrospective analysis of 285 patients. Gynecol Oncol 71:431– 436, 1998 12. Schwartz PE, Rutherford TJ, Chambers JT, Kohorn EI, Thiel RP: Neoadjuvant chemotherapy for advanced ovarian cancer: long-term survival. Gynecol Oncol 72:93–99,1999 13. Peipert JF, Sweeney PJ: Diagnostic testing in obstetrics and gynecology: a clinician’s guide. Obstet Gynecol 82:619 – 623, 1993
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