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Preoperative Prediction of Optimal Resectability in Advanced Ovarian Cancer Using CA-125
Gynecologic Oncology 77, 225–226 (2000) doi:10.1006/gyno.2000.5808, available online at http://www.idealibrary.com on
EDITORIAL Preoperative Prediction of Optimal Resectability in Advanced Ovarian Cancer Using CA-125 Jonathan S. Berek, M.D. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, UCLA School of Medicine, Los Angeles, California 90095-1740
Advanced epithelial ovarian cancer represents the greatest clinical challenge in gynecologic oncology. Surgery followed by appropriate chemotherapy is considered the cornerstone of appropriate therapy for the disease [1]. The International Federation of Obstetrics and Gynecology mandates surgical staging and appropriate biopsy to ascertain the correct diagnosis and to determine the histopathologic extent of the disease [2]. The value of this approach is that it allows accurate identification of those patients who have nonmetastatic cancer and therefore may not benefit from therapy [3, 4], and it permits the resection of both the pelvic disease and metastatic implants [1]. Combination chemotherapy with paclitaxel and carboplatin has emerged as the best treatment for the majority of epithelial malignancies [5, 6]. Over the past 25 years, it has become established, largely through retrospective analysis, that optimal resection of metastatic epithelial ovarian cancer has a profound impact on the survival of patients with advanced stage disease [7–10]. In the single prospective trial of “interval” cytoreductive surgery, there was a 40% reduction in mortality in most patients who underwent the debulking, even though they were considered unresectable prior to chemotherapy [11]. The results of this trial suggest that the standard of care for women with stage III epithelial ovarian cancer should include an attempt at the optimal resection of the disease [12]. There has always been some controversy about the interplay between the surgeon’s effort to resect the disease (i.e., feasibility and aggressiveness of the effort) vs the inherent resectability of the malignancy (i.e., features that may be biologically programmed into the tumor) [13, 14]. It has been well recognized that there are limitations to cytoreductive surgery in advanced epithelial ovarian cancer, including the extent of metastatic disease and the location of some of these implants [15, 16]. Women whose tumors are extensively infiltrating the liver parenchyma or the porta hepatis and those who have large bulky disease implanted on the diaphragm are often unresectable. There is a correlation with features that predict tumor biology; i.e., tumors that tend to be poorly differentiated and present with widespread metastasis correlate with the level of CA-125 [16]. In this issue of Gynecologic Oncology, Chi and colleagues [17] report their retrospective analysis of 100 consecutive women with Stage III ovarian carcinoma who had a serum CA-125 drawn prior to exploratory surgery and then had an attempted primary cytoreductive operation. Optimal cytoreduction was obtained in only
45% of these women. The authors indicate that with a 500 units/ml cutoff value of CA-125, the resectability is 73% in those women whose CA-125 level is less than 500 units/ml compared to only 22% when the CA-125 is higher than 500 units/ml. The authors conclude that the preoperative CA-125 is valuable in terms of predicting the likelihood of optimally resecting primary metastatic epithelial ovarian cancer. The principal finding that resectability is correlated with the level of CA-125 is not surprising, because in prior series, the CA-125 level correlated with the extent of disease and the extent of bulky disease correlated with resectability [18 –20]. The use of the “risk of ovarian cancer” (ROC) paradigm permits a reasonable degree of accuracy in the analysis of the CA-125 data [19]. Furthermore, the authors suggest that using the CA-125 to make the decision whether to explore a woman with probable metastatic ovarian cancer may help to identify a candidate for “alternative approaches,” rather than subjecting her to a traditional laparotomy and attempt at a primary cytoreductive operation. They suggest that women who have CA-125 levels above 500 units/ml should be spared the laparotomy and undergo a laparoscopy followed by “neoadjuvant chemotherapy.” The problem with this supposition is that the data imply that (1) we know the sensitivity of initial laparoscopy to evaluate for resectibility, and (2) we know that neoadjuvant chemotherapy is a suitable alternative for the disease. While the answers to these questions are still being debated, it would be premature to abandon the consensus that a laparotomy should be avoided in these women. An optimal debulking of ovarian cancer should be offered to all patients who are medically fit, giving them the opportunity of potent benefit by the optimal cytoreduction prior to chemotherapy. The laparoscope, although a useful tool in epithelial ovarian cancer, has many attendant problems, including issues of visibility in women with carcinomatosis [21]. Therefore, it may be difficult to truly assess resectability. The use of neoadjuvant chemotherapy (although supported by the preliminary evidence as a reasonable alternative in some women to the usual paradigm of surgery first, chemotherapy second) remains to be better defined in the armamentarium for the treatment of this disease [22, 23]. The median survivals of those women who are treated with neoadjuvant chemotherapy may be shorter than those of women who undergo aggressive treatment with primary surgery followed by chemotherapy. In addition to the retrospective nature of this study, only a
225
0090-8258/00 $35.00 Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
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EDITORIAL
relatively small proportion of patients in this group had an optimal resection (45%). This percentage is lower than those reported by several other authors and may represent a group of patients with a high likelihood of adverse prognostic criteria [8, 9]. Indeed, in another paper from the authors’ institution, the optimal resection rate in women with Stage IV disease was about the same [24]. Women with Stage IV disease who undergo optimal resection of their disease also appear to have a better survival than those who do not undergo resection [24, 25]. Also, 20% of the patients studied had either undifferentiated or clear cell carcinomas, lesions of extremely poor prognosis, or a higher likelihood of being unresectable. Although the level of CA-125 correlated with resectability, the proportion found to be resectable is considerably lower because of the skewed population. As the authors indicate, withholding an attempt at cytoreduction may deprive some patients of a procedure that could significantly prolong their survival. The best cutoff level for CA-125 to predict optimal resectability may be higher than the authors have presented. The best cutoff may depend on one’s philosophy. If one can optimally debulk only 25–30% of women who are explored, it may be worth the attempt for that specific group of women. Using the author’s data, this rate of optimal resection can occur with a CA-125 cutoff of 1000 –2000 units/ml based on the sensitivity of the prediction. Given all these issues, this study should be viewed as a provocative retrospective analysis that should lead to prospective studies to determine the applicability of CA-125 to predicting resectibility, to clarifying the use of the laparoscope to predict resectibility, and to developing well-designed trials of neoadjuvant therapy. Such studies, carefully defined, could provide a more reliable means of predicting which patients might best be treated in a manner different from the established paradigm. Until then, gynecologic oncologists should use the sum of all criteria to determine whether women (who are otherwise medically fit and healthy) should undergo an exploratory surgery to attempt to cytoreduce their tumor until more data are available. Those women who have a CA-125 greater than 500 units/ml should not be deprived the potentially optimal cytoreductive operation based solely on that criterion.
6.
7. 8.
9.
10.
11.
12. 13. 14. 15.
16. 17.
18.
19.
20.
REFERENCES 1. Berek JS, Bertlesen K, du Bois A, Brady MF, Carmichael J, Eisenhauer EA, et al.: Advanced epithelial ovarian cancer: 1998 consensus statement. Ann Oncol 10 [Suppl 1]:87–92, 1999
21. 22.
2. Pecorelli S, Odicino F, Maisonneuve P, Creasman W, Shepard J, Sideri M, et al.: Carcinoma of the ovary: Annual Report on the Results of Treatment of Gynaecological Cancer. J Epidemiol Biostat 3:75–102, 1998 3. Young RC, Walton LA, Ellenberg SS, Homesley HD, Wilbanks GD, Decker DG, et al.: Adjuvant therapy in stage I and stage II epithelial ovarian cancer: results of two prospective randomized trials. N Engl J Med 322:1021–1027, 1990 4. Berek JS: Adjuvant therapy for early-stage ovarian cancer. N Engl J Med 322:1076 –1078, 1990 5. McGuire WP, Hoskins WJ, Brady MF, Kucera, Partridge EE, Look KY, et al.: Cyclophosphamide and cisplatin compared with paclitaxel and
23.
24. 25.
cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1– 6, 1996 Du Bois A, Lueck HG, Meier W, Moebus V, Costa SD, Bauknecht T, et al.: Cisplatin/paclitaxel versus carboplatin/paclitaxel in ovarian cancer: update of an Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Study Group trial. Proc Am Soc Clin Oncol 35:1374(abst), 1999 Griffiths CT: Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr 42:101–104, 1975 Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Elashoff RM: Primary cytoreductive surgery for epithelial ovarian cancer. Obstet Gynecol 61: 413– 420, 1983 Hoskins WJ, Bundy BN, Thigpen JT, Omura GA: The influence of cytoreductive surgery on recurrence-free interval and survival in small volume state III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 47:159 –166, 1942 Hoskins WJ, McGuire WP, Brady MF, Homesley HD, Creasman WT, Berman M, et al.: 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 –979, 1994 van der Burg MEL, van Lent M, Buyse M, Koblerska A, Columbo N, Favlli G, et al.: The effect of debulking surgery after induction chemotherapy on the prognosis in advanced ovarian cancer. N Engl J Med 332:629 – 634, 1995 Berek JS: Interval debulking of ovarian cancer: an interim measure. N Engl J Med 332:675– 677, 1995 Berek JS: Complete debulking of advanced ovarian cancer. Cancer J Aci Am 2:134 –135, 1996 Farias-Eisner R, Kim YB, Berek JS: Surgical management of ovarian cancer. Semin Surg Oncol 10:268 –275, 1994 Farlas-Eisner R, Teng F, Oliveira M, Leuchter R, Karlan B, Lagasse LD, Berek JS: The influence of tumor grade, distribution and extent of carcinomatosis in minimal residual epithelial ovarian cancer after optimal primary cytoreductive surgery. Gynecol Oncol 55:108 –110, 1994 Hacker NF: Cytoreduction for advanced ovarian cancer in perspective. Gynecol Cancer 6:159 –160, 1996 Chi DS, Venkatraman ES, Masson V, Hoskins WJ: The ability of preoperative serum CA-125 to predict optimal primary tumor cytoreduction in stage III epithelial ovarian carcinoma. Gynecol Oncol 77:227–231, 2000 Berek JS, Bast RC Jr.: Ovarian cancer screening: the use of serial complementary tumor markers to improve sensitivity and specificity for early detection. Cancer 76:2092–2096, 1995 Skates SJ, Xu FJ, Yu YH, Sjovall K, Einhorn N, Chang Y, et al.: Towards an optimal algorithm for ovarian cancer screening with longitudinal tumour markers. Cancer 76:2004 –2010, 1995 Berek JS, Knapp RC, Malkasian GD, Lavin PT, Whitney C, Niloff JM, et al.: CA 125 serum levels correlated with second-look operations among ovarian cancer patients. Obstet Gynecol 67:685– 698, 1986 Berek JS, Griffiths CT, Leventhal JM: Laparoscopy for second-look evaluation in ovarian cancer. Obstet Gynecol 58:192–198, 1981 Vergote I, De Wever I, Tjalma W, Van Grambeeren 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 Schwartz PE, Rutjherford TJ, Chambers JT, Kohorn EI, Theil RP: Neoadjuvant chemotherapy for advanced ovarian cancer: long-term survival. Gynecol Oncol 72:93–99, 1999 Curtin JP, Malik R, Venkatraman ES, Barakat RR, Hoskins WJ: Stage IV ovarian cancer: impact of surgical debulking. Gynecol Oncol 64:9 –12, 1997 Bristow R, Montz FJ, Lagasse LD, Leuchter RS, Karlan BY: Survival impact of surgical cytoreduction in stage IV epithelial ovarian cancer. Gynecol Oncol 72:278 –287, 1999
EDITORIAL Preoperative Prediction of Optimal Resectability in Advanced Ovarian Cancer Using CA-125 Jonathan S. Berek, M.D. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, UCLA School of Medicine, Los Angeles, California 90095-1740
Advanced epithelial ovarian cancer represents the greatest clinical challenge in gynecologic oncology. Surgery followed by appropriate chemotherapy is considered the cornerstone of appropriate therapy for the disease [1]. The International Federation of Obstetrics and Gynecology mandates surgical staging and appropriate biopsy to ascertain the correct diagnosis and to determine the histopathologic extent of the disease [2]. The value of this approach is that it allows accurate identification of those patients who have nonmetastatic cancer and therefore may not benefit from therapy [3, 4], and it permits the resection of both the pelvic disease and metastatic implants [1]. Combination chemotherapy with paclitaxel and carboplatin has emerged as the best treatment for the majority of epithelial malignancies [5, 6]. Over the past 25 years, it has become established, largely through retrospective analysis, that optimal resection of metastatic epithelial ovarian cancer has a profound impact on the survival of patients with advanced stage disease [7–10]. In the single prospective trial of “interval” cytoreductive surgery, there was a 40% reduction in mortality in most patients who underwent the debulking, even though they were considered unresectable prior to chemotherapy [11]. The results of this trial suggest that the standard of care for women with stage III epithelial ovarian cancer should include an attempt at the optimal resection of the disease [12]. There has always been some controversy about the interplay between the surgeon’s effort to resect the disease (i.e., feasibility and aggressiveness of the effort) vs the inherent resectability of the malignancy (i.e., features that may be biologically programmed into the tumor) [13, 14]. It has been well recognized that there are limitations to cytoreductive surgery in advanced epithelial ovarian cancer, including the extent of metastatic disease and the location of some of these implants [15, 16]. Women whose tumors are extensively infiltrating the liver parenchyma or the porta hepatis and those who have large bulky disease implanted on the diaphragm are often unresectable. There is a correlation with features that predict tumor biology; i.e., tumors that tend to be poorly differentiated and present with widespread metastasis correlate with the level of CA-125 [16]. In this issue of Gynecologic Oncology, Chi and colleagues [17] report their retrospective analysis of 100 consecutive women with Stage III ovarian carcinoma who had a serum CA-125 drawn prior to exploratory surgery and then had an attempted primary cytoreductive operation. Optimal cytoreduction was obtained in only
45% of these women. The authors indicate that with a 500 units/ml cutoff value of CA-125, the resectability is 73% in those women whose CA-125 level is less than 500 units/ml compared to only 22% when the CA-125 is higher than 500 units/ml. The authors conclude that the preoperative CA-125 is valuable in terms of predicting the likelihood of optimally resecting primary metastatic epithelial ovarian cancer. The principal finding that resectability is correlated with the level of CA-125 is not surprising, because in prior series, the CA-125 level correlated with the extent of disease and the extent of bulky disease correlated with resectability [18 –20]. The use of the “risk of ovarian cancer” (ROC) paradigm permits a reasonable degree of accuracy in the analysis of the CA-125 data [19]. Furthermore, the authors suggest that using the CA-125 to make the decision whether to explore a woman with probable metastatic ovarian cancer may help to identify a candidate for “alternative approaches,” rather than subjecting her to a traditional laparotomy and attempt at a primary cytoreductive operation. They suggest that women who have CA-125 levels above 500 units/ml should be spared the laparotomy and undergo a laparoscopy followed by “neoadjuvant chemotherapy.” The problem with this supposition is that the data imply that (1) we know the sensitivity of initial laparoscopy to evaluate for resectibility, and (2) we know that neoadjuvant chemotherapy is a suitable alternative for the disease. While the answers to these questions are still being debated, it would be premature to abandon the consensus that a laparotomy should be avoided in these women. An optimal debulking of ovarian cancer should be offered to all patients who are medically fit, giving them the opportunity of potent benefit by the optimal cytoreduction prior to chemotherapy. The laparoscope, although a useful tool in epithelial ovarian cancer, has many attendant problems, including issues of visibility in women with carcinomatosis [21]. Therefore, it may be difficult to truly assess resectability. The use of neoadjuvant chemotherapy (although supported by the preliminary evidence as a reasonable alternative in some women to the usual paradigm of surgery first, chemotherapy second) remains to be better defined in the armamentarium for the treatment of this disease [22, 23]. The median survivals of those women who are treated with neoadjuvant chemotherapy may be shorter than those of women who undergo aggressive treatment with primary surgery followed by chemotherapy. In addition to the retrospective nature of this study, only a
225
0090-8258/00 $35.00 Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
226
EDITORIAL
relatively small proportion of patients in this group had an optimal resection (45%). This percentage is lower than those reported by several other authors and may represent a group of patients with a high likelihood of adverse prognostic criteria [8, 9]. Indeed, in another paper from the authors’ institution, the optimal resection rate in women with Stage IV disease was about the same [24]. Women with Stage IV disease who undergo optimal resection of their disease also appear to have a better survival than those who do not undergo resection [24, 25]. Also, 20% of the patients studied had either undifferentiated or clear cell carcinomas, lesions of extremely poor prognosis, or a higher likelihood of being unresectable. Although the level of CA-125 correlated with resectability, the proportion found to be resectable is considerably lower because of the skewed population. As the authors indicate, withholding an attempt at cytoreduction may deprive some patients of a procedure that could significantly prolong their survival. The best cutoff level for CA-125 to predict optimal resectability may be higher than the authors have presented. The best cutoff may depend on one’s philosophy. If one can optimally debulk only 25–30% of women who are explored, it may be worth the attempt for that specific group of women. Using the author’s data, this rate of optimal resection can occur with a CA-125 cutoff of 1000 –2000 units/ml based on the sensitivity of the prediction. Given all these issues, this study should be viewed as a provocative retrospective analysis that should lead to prospective studies to determine the applicability of CA-125 to predicting resectibility, to clarifying the use of the laparoscope to predict resectibility, and to developing well-designed trials of neoadjuvant therapy. Such studies, carefully defined, could provide a more reliable means of predicting which patients might best be treated in a manner different from the established paradigm. Until then, gynecologic oncologists should use the sum of all criteria to determine whether women (who are otherwise medically fit and healthy) should undergo an exploratory surgery to attempt to cytoreduce their tumor until more data are available. Those women who have a CA-125 greater than 500 units/ml should not be deprived the potentially optimal cytoreductive operation based solely on that criterion.
6.
7. 8.
9.
10.
11.
12. 13. 14. 15.
16. 17.
18.
19.
20.
REFERENCES 1. Berek JS, Bertlesen K, du Bois A, Brady MF, Carmichael J, Eisenhauer EA, et al.: Advanced epithelial ovarian cancer: 1998 consensus statement. Ann Oncol 10 [Suppl 1]:87–92, 1999
21. 22.
2. Pecorelli S, Odicino F, Maisonneuve P, Creasman W, Shepard J, Sideri M, et al.: Carcinoma of the ovary: Annual Report on the Results of Treatment of Gynaecological Cancer. J Epidemiol Biostat 3:75–102, 1998 3. Young RC, Walton LA, Ellenberg SS, Homesley HD, Wilbanks GD, Decker DG, et al.: Adjuvant therapy in stage I and stage II epithelial ovarian cancer: results of two prospective randomized trials. N Engl J Med 322:1021–1027, 1990 4. Berek JS: Adjuvant therapy for early-stage ovarian cancer. N Engl J Med 322:1076 –1078, 1990 5. McGuire WP, Hoskins WJ, Brady MF, Kucera, Partridge EE, Look KY, et al.: Cyclophosphamide and cisplatin compared with paclitaxel and
23.
24. 25.
cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1– 6, 1996 Du Bois A, Lueck HG, Meier W, Moebus V, Costa SD, Bauknecht T, et al.: Cisplatin/paclitaxel versus carboplatin/paclitaxel in ovarian cancer: update of an Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Study Group trial. Proc Am Soc Clin Oncol 35:1374(abst), 1999 Griffiths CT: Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr 42:101–104, 1975 Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Elashoff RM: Primary cytoreductive surgery for epithelial ovarian cancer. Obstet Gynecol 61: 413– 420, 1983 Hoskins WJ, Bundy BN, Thigpen JT, Omura GA: The influence of cytoreductive surgery on recurrence-free interval and survival in small volume state III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 47:159 –166, 1942 Hoskins WJ, McGuire WP, Brady MF, Homesley HD, Creasman WT, Berman M, et al.: 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 –979, 1994 van der Burg MEL, van Lent M, Buyse M, Koblerska A, Columbo N, Favlli G, et al.: The effect of debulking surgery after induction chemotherapy on the prognosis in advanced ovarian cancer. N Engl J Med 332:629 – 634, 1995 Berek JS: Interval debulking of ovarian cancer: an interim measure. N Engl J Med 332:675– 677, 1995 Berek JS: Complete debulking of advanced ovarian cancer. Cancer J Aci Am 2:134 –135, 1996 Farias-Eisner R, Kim YB, Berek JS: Surgical management of ovarian cancer. Semin Surg Oncol 10:268 –275, 1994 Farlas-Eisner R, Teng F, Oliveira M, Leuchter R, Karlan B, Lagasse LD, Berek JS: The influence of tumor grade, distribution and extent of carcinomatosis in minimal residual epithelial ovarian cancer after optimal primary cytoreductive surgery. Gynecol Oncol 55:108 –110, 1994 Hacker NF: Cytoreduction for advanced ovarian cancer in perspective. Gynecol Cancer 6:159 –160, 1996 Chi DS, Venkatraman ES, Masson V, Hoskins WJ: The ability of preoperative serum CA-125 to predict optimal primary tumor cytoreduction in stage III epithelial ovarian carcinoma. Gynecol Oncol 77:227–231, 2000 Berek JS, Bast RC Jr.: Ovarian cancer screening: the use of serial complementary tumor markers to improve sensitivity and specificity for early detection. Cancer 76:2092–2096, 1995 Skates SJ, Xu FJ, Yu YH, Sjovall K, Einhorn N, Chang Y, et al.: Towards an optimal algorithm for ovarian cancer screening with longitudinal tumour markers. Cancer 76:2004 –2010, 1995 Berek JS, Knapp RC, Malkasian GD, Lavin PT, Whitney C, Niloff JM, et al.: CA 125 serum levels correlated with second-look operations among ovarian cancer patients. Obstet Gynecol 67:685– 698, 1986 Berek JS, Griffiths CT, Leventhal JM: Laparoscopy for second-look evaluation in ovarian cancer. Obstet Gynecol 58:192–198, 1981 Vergote I, De Wever I, Tjalma W, Van Grambeeren 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 Schwartz PE, Rutjherford TJ, Chambers JT, Kohorn EI, Theil RP: Neoadjuvant chemotherapy for advanced ovarian cancer: long-term survival. Gynecol Oncol 72:93–99, 1999 Curtin JP, Malik R, Venkatraman ES, Barakat RR, Hoskins WJ: Stage IV ovarian cancer: impact of surgical debulking. Gynecol Oncol 64:9 –12, 1997 Bristow R, Montz FJ, Lagasse LD, Leuchter RS, Karlan BY: Survival impact of surgical cytoreduction in stage IV epithelial ovarian cancer. Gynecol Oncol 72:278 –287, 1999