- Email: [email protected]
A multicenter study of CA 125 level as a predictor of non-optimal primary cytoreduction of advanced epithelial ovarian cancer
EJSO (2005) 31, 1006–1010
www.ejso.com
A multicenter study of CA 125 level as a predictor of non-optimal primary cytoreduction of advanced epithelial ovarian cancer O. Gemera,*, M. Luriana, M. Gdalevichb, V. Kapustiana, E. Piurac, D. Schneiderd, O. Laviee, T. Levyf, A. Fishmang, R. Dganih, H. Levavii, U. Bellerj a
Department of Obstetrics and Gynecology Barzilai Medical Center, 78306 Ashkelon, Ben Gurion University of the Negev, Israel b District Health Office, Ashkelon, Israel c Soroka Medical Center, Beer Sheva, Israel d Assaf Harofe Medical Center, Tzrifin, Israel e Carmel Medical Center, Haifa, Israel f Wolfson Medical Center, Holon, Israel g Meir Medical Center, Kfar Saba, Israel h Kaplan Medical Center, Rehovot, Israel i Rabin Medical Center, Petah Tikva, Israel j Shaare Zedek Medical Center, Jerusalem, Israel Accepted for publication 18 May 2005 Available online 7 July 2005
KEYWORDS Epithelial ovarian cancer; CA 125; Cytoreduction; Prediction
Abstract Aims: To provide a large database of pre-operative CA 125 levels which may predict inappropriate cytoreductive surgery in patients with advanced epithelial ovarian cancer. Methods: A multicenter review of the records of 424 patients with FIGO stage III and IV epithelial ovarian cancer of patients who underwent primary cytoreductive surgery was performed. The validity of pre-operative CA 125 level measurement as a single predictor of the possibility to achieve only suboptimal cytoreduction was evaluated by calculating the sensitivity and the specificity of various cut-off values. The relative importance of different cut-off values in achieving the best predictive validity was assessed by a receiver operating characteristics (ROC) curve. Results: Optimal cytoreduction (largest diameter of residual tumour %1 cm) was achieved in 242 patients. The median CA 125 level in optimally cytoreduced patients was lower than in those patients suboptimally debulked (304 vs 863 U/mL; p!0.001). The area under the ROC curve was 0.65 (95% confidence interval, 0.60–0.71) and the
* Corresponding author. Tel.:C972 86745937; fax: C972 86745331. E-mail address: [email protected] (O. Gemer).
0748-7983/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2005.05.009
CA 125 level as a predictor of optimal cytoreduction
1007
CA 125 threshold derived from the ROC was 400 U/mL. The accuracy of the test at this level was 62%. Conclusions: The clinical applicability of the ROC derived CA 125 threshold is limited. The data accrued in the study provides a basis for decision-making regarding the place of primary surgery various CA 125 levels. Q 2005 Elsevier Ltd. All rights reserved.
Introduction The benefits of tumour cytoreduction in patients with advanced ovarian carcinoma are well recognized.1–4 Numerous studies, however, have demonstrated that tumour debulking improves survival only if optimal residual disease can be attained.3 As the reported optimal cytoreduction rates generally vary between 40–80%,5 the traditional approach of initial laparotomy does not benefit a significant proportion of the patients. On the other hand, withholding initial surgical attempt may deprive patients from a procedure that could substantially increase their survival.4 Women, in whom optimal cytoreduction is not attained, experience surgical morbidity without the compensatory survival advantage associated with an optimal result. As alternative treatment programs, such as neoadjuvant chemotherapy for patients with advanced disease at high risk for non-optimal debulking, are being studied,5–7 pre-operative criteria for predicting non-optimal cytoreduction are most valuable. In attempting to predict non-optimal cytoreduction two approaches have been advanced. A few studies relying on computerized tomography have defined radiological criteria which were found to be predictive of non-optimal debulking.8–11 In these studies various radiological features, or models in which they were accrued into an index, were able to predict the surgical outcome with an accuracy of 79–93%. However, the agreement between the reports, on predictive accuracy of the various radiological characteristics, was limited. The other approach has been to utilize the tumour marker CA 125 level which is known to correlate with tumour burden.12 While all studies of CA 125 levels were consistent in regard to the presence of a correlation between the tumour marker level and resectability, they differed in the threshold cut-off levels attained and their interpretation of the clinical utility.13–20 The CA 125 cut-off levels varied between 500 and 912 IU and the accuracy of the test at the threshold level ranged between 56 and 78%.13–20 These pre-operative CA 125 studies arrived at the threshold level utilizing a receiver operating curve (ROC) methodology. At the ROC
derived cut-off level which allowed equal weight for false-positive and false-negative outcome the clinical utility of the test is debatable. The purpose of this study is to provide a large multiinstitutional derived database for determining CA 125 levels which may predict unnecessary exploration rates in patients with advanced ovarian cancer.
Patients and methods A multicenter retrospective review of the records of 424 patients with International Federation of Gynecology and Obstetrics (FIGO) stage III and IV invasive epithelial ovarian cancer was made. Only patients who underwent an attempt at primary cytoreductive surgery were included. Data obtained from the charts included age, preoperative serum CA 125 levels, operative findings, procedure performed, residual disease at the end of the procedure and histology report. Optimal cytoreduction was defined in accordance with Gynecology Oncology Group (GOG) criteria when the diameter of the largest residual nodule measured less than or equal to 1 cm.2 The univariate analysis of the association between independent variables, such as age, tumour grade and histological type and the debulking result was performed by calculating the appropriate odds ratio (OR) and the corresponding 95% confidence interval (CI) for each. The comparison between CA 125 measurements in the two groups, according to the debulking result was done utilizing a Mann–Whitney U-test, a non-parametric approach, as the distribution of the measurements was substantially different from the normal distribution. The validity of pre-operative CA 125 level measurement as a predictor of suboptimal cytoreduction was evaluated by calculating the sensitivity and the specificity of various cut-off values. The sensitivity was defined as the percentage of patients with suboptimal cytoreduction, who had CA 125 level of above the given cut-off. Specificity was defined as the percentage of optimally
1008 Table 1
O. Gemer et al. Distribution of patients by age tumour histology, FIGO grade and debulking status
Age !60 R60 Histological type Papillary serous Mucinous Endometroid Other Grade 1 2 3
Suboptimal
Optimal
Total
Odds ratio (95% confidence interval)
61 121
119 123
180 244
Reference 1.92 (1.27–2.92)
136 7 12 25
195 7 18 21
331 14 30 46
Reference 1.43 (0.42–4.91) 0.96 (0.46–2.18) 1.71 (0.88–3.35)
8 24 140
18 35 173
26 59 313
Reference 1.54 (0.53–4.78) 1.82 (0.73–4.18)
cytoreduced patients who had CA 125 levels below the cut-off value.
ROC analysis The relative importance of different cut-off values in achieving the best predictive validity was assessed by constructing a receiver operating characteristics (ROC) curve, which plots the sensitivity on the y-axis and the false-positive rate (defined as 1-specificity) along the x-axis. The area under the ROC curve corresponds to the overall predictive validity. A value of 1 corresponds to a perfect accuracy measure and a value of 0.5 indicates pure chance. The point on the curve closest to the top left corner of the graph is the point where the sum of sensitivity and specificity is the highest. The closer this point is to the top left corner, the better the test (assuming false-negatives and false-positives are equally important). All computations were performed using the PEPI software for epidemiological analysis (Ver. 3, Stone Mountain, Georgia: USD Inc., 1999).
Results The median patient’s age was 62 years (range 25– 87). The median pre-operative serum CA 125 level was 495 U/mL (range 3–52,777), and it was elevated (O35 U/mL) in 392 patients. Twenty-five patients had stage III A disease, 75 had stage III B, 296 had stage III C and 28 had stage IV. Histologicaly, 331cases were papillary serous, 30 were endometroid 14 were mucinous and 46 had other histology. Twenty-six patients had grade 1 tumour, 59 had grade 2 and 313 had grade 3.
Optimal cytoreduction (largest diameter of residual tumour %1 cm) was reported in 242 patients. The distribution of patients by age, histological type, tumour grade and debulking status is shown in Table 1. A significantly greater proportion of patients younger than 60 were optimally debulked. The median CA 125 level in optimally cytoreduced patients was lower than in those patients debulked suboptimally (304 vs 863 U/mL, respectively; Mann–Whitney zZK5.51; p!0.001). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of performing non-optimal cytoreduction at various CA 125 threshold levels is shown in Table 2. Fig. 1 shows the ROC generated by the data; the area under the curve was 0.655 (95% confidence interval 0.603–0.708, p!0.0001) representing a significant difference from the hypothetical 458 ‘fifty-fifty’ Table 2 Prediction of suboptimal cytoreductive surgery at various CA 125 levels CA 125 cut-off level (U/ mL)
Sensitivity (%)
Specificity (%)
Positive predictive value
Negative predictive value
100 200 300 400 500 700 1000 1500 2500 5000 7500
89.0 80.2 74.7 69.2 63.2 53.3 45.1 30.8 18.1 5.5 3.8
26.4 38.8 49.6 57.0 61.6 66.1 75.2 84.7 90.5 97.5 97.9
47.6 51.8 52.7 54.8 55.3 54.2 57.7 60.2 58.9 62.5 58.3
76.2 74.6 72.3 71.1 69.0 65.3 64.5 61.9 59.5 57.8 57.5
CA 125 level as a predictor of optimal cytoreduction
Figure 1 Receiver operating characteristics curve (ROC) of correlation between sensitivity and falsepositive (1-specificity) rate for non-optimal cytoreductive surgery using each CA 125 level as a cut-off point.
line. The point on the curve closest to the upper left corner corresponds to a threshold level of 400 U/ mL. The accuracy of the test at this level was 62%.
Discussion This study corroborates the known relationship between CA 125 levels and outcome of cytoreductive surgery.13–20 As others,18 we found older age to be significantly associated with non-optimal debulking. A trend (not reaching statistical significance), associating non-optimal cytoreduction and higher tumour grade was noted. Statistically significant association of higher tumour grade and non-optimal debulking have been previously reported,18 as well as positive correlation between tumour grade and CA 125 levels.15,16 It is well recognized that the ability to perform optimal cytoreduction of advanced ovarian cancer reflects interplay between inherent biological features of the malignancy and surgical efforts.21 While optimal debulking rates of 98% have been reported,22 these rates which constitute the experience of a single center attest to a highly aggressive surgical attempt which may be associated with significant morbidity. Although the potential salutary value of neo-adjuvant chemotherapy in terms of survival benefit are still being studied,5 it has been appreciated that less radical surgery is needed for optimal cytoreduction if it follows chemotherapy.23,24,16 Under these circumstances, a triage mechanisms which will
1009 have wide applicability, and will allow a proportion of patients to be spared a futile surgery, yet compromise the benefits of primary surgery from relatively a small number of patients, seems reasonable. Some generalizations can be made on the studies utilizing CA 125 to predict non-optimal debulking.13–20 Most series report a median CA 125 of approximately 500 U/ml (the higher median CA 125 in some series may be a reflection of their being referral centers) and the optimal debulking rate in most centers ranges from 50 to 60%. The ROC derived CA 125 threshold level for non-optimal debulking in most series is also 500 U/mL; the area under the ROC ranging from 0.65 to 0.89. If this threshold level is used to select patients for surgery, approximately half of the patients will not be candidates for a primary surgical attempt. The limited usefulness of using pre-operative CA 125 for triage has been most stressed by two CA 125 studies,17,19 and by the work of Bristow et al.10 in which the pre-operative CA 125 level was not included among the radiological index parameters, because it was not sufficiently predictive of surgical outcome. This study by its size further confirms the limitation of the potential use ROC derived CA 125 cut-off level as a predictor of optimal surgery. Several authors have suggested that an appropriate CA 125 cut-off level would be between 1000 and 1500 U/mL.16,25 The data accrued this study may provide a basis for decision-making regarding the place of primary surgery at all CA 125 levels which may serve the expectations from primary cytoreductive surgery of both surgeon and the patient.
References 1. Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Elashoff RM. Primary cytoreductive surgery for epithelial ovarian cancer. Obstet Gynecol 1983;61:413–20. 2. Hoskins WJ, Bundy BN, Thigpen JT, Omura GA. The influence of cytoreductive surgery on recurrence-free interval and survival in small volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 1992;47: 159–66. 3. 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 1994;170:974–9. 4. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20:1248–59. 5. Van Der Burg ME, Vergote I, Gynecological Cancer Group of the EORTC. The role of interval debulking surgery in ovarian cancer. Curr Oncol Rep 2003;5:473–81.
1010 6. Van der Burg ME, van Lent M, Buyse M, Kobierska A, Colombo N, Favalli G, et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gyncological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med 1995;332:629–34. 7. Vergote I, De Wever I, Tjaima W, Van Gramberen M, Decloedt J, Van Dam P. Neoadjuvant chemotherapy of primary debulking surgery in advanced ovarian carcinoma: a retrospective analysis of 285 patients. Gynecol Oncol 1998; 71:431–6. 8. Nelson BE, Rosenfield AT, Schwartz PE. Preoperative abdominopelvic computed tomographic prediction of optimal cytoreduction in epithelial ovarian carcinoma. J Clin Oncol 1993;11:166–72. 9. Meyer JI, Kennedy AW, Freedman R, Ayoub A, Zepp RC. Ovarian carcinoma: value of CT in predicting success of debulking surgery. AJR Am J Roentgenol 1995;165:875–8. 10. Bristow RE, Duska LR, Lambrou NC, Fishman EK, O’Neill MJ, Trimble EL, et al. A model for predicting surgical outcome in patients with advanced ovarian carcinoma using computed tomography. Cancer 2000;89:1532–40. 11. Dowdy SC, Mullany SA, Brandt KR, Huppert BJ, Cliby WA. The utility of computed tomography scans in predicting suboptimal cytoreductive surgery in women with advanced ovarian carcinoma. Cancer 2004;101:346–52. 12. Geisler JP, Miller GA, Lee TH, Harwood RM, Wiemann MC, Geisler HE. Relationship of preoperative serum CA-125 to epithelial ovarian carcinoma. J Reprod Med 1996;41:140–2. 13. Chi DS, Venkatraman ES, Masson V, Hoskins WJ. The ability of preoperative serum CA-125 to predict optimal primary tumour cytoreduction in stage III epithelial ovarian carcinoma. Gynecol Oncol 2000;77:227–31. 14. Gemer O, Segal S, Kopmar A. Preoperative CA-125 level as a predictor of non optimal cytoreduction of advanced epithelial ovarian cancer. Acta Obstet Gynecol Scand 2001; 80:583–5. 15. Cooper BC, Sood AK, Davis CS, Ritchie JM, Sorosky JI, Anderson B, et al. Preopetrative CA 125 levels: an independent prognostic factor for epithelial ovarian cancer. Obstet Gynecol 2002;100:59–64.
O. Gemer et al. 16. Saygili U, Guclu S, Uslu T, Erten O, Demir N, Onvural A. Can serum CA-125 levels predict the optimal primary cytoreduction in patients with advanced ovarian carcinoma? Gynecol Oncol 2002;86:57–61. 17. Memarzadeh S, Lee SB, Berek JS, Farias-Eisner R. CA125 levels are a weak predictor of optimal cytoreductive surgery in patients with advanced epithelial ovarian cancer. Int J Gynecol Cancer 2003;13:120–4. 18. Brockbank EC, Ind TEJ, Barton DP, Shepherd JH, Gore ME, A’Hern R, et al. Preoperative predictors of suboptimal primary surgical cytoreduction in women with clinical evidence of advanced primary epithelial ovarian cancer. Int J Gynecol Cancer 2004;14:42–50. 19. Alca ´zer JI, Miranda D, Unanue A, Novoa E, Alema ´n A, Madariaga L. C-125 levels in predicting optimal cytoreductive surgery in patients with advanced epithelial ovarian carcinoma. Int J Gynecol Obstet 2004;84:173–4. 20. Obeidat B, Latimer J. Can optimal primary cytoreduction be predicted in advanced stage epithelial ovarian cancer? Role of preoperative serum CA-125 level Gynecol Obstet Invest 2004;57:153–6. 21. Berchuck A, Iversen ES, Lancaster HK, West M, Nevins JR, Marks JR. Prediction of optimal versus suboptimal cytoreduction of advanced-stage serous ovarian cancer with the use of microarrays. Am J Obstet Gynecol 2004;190:910–23. 22. Eisenkop SM, Friedman RL, Wang HJ. Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol 1998;69:103–8. 23. Schwartz PE, Rutherford TJ, Chambers JT, Kohorn EL, Thiel RP. Neoadjuvant chemotherapy for advanced ovarian cancer: long-term survival. Gynecol Oncol 1999;72:93–9. 24. Ansquer Y, Leblanc E, Clough K, Morice P, Dauplat J, Mathevet P, et al. Neoadjuvant chemotherapy for unresectable ovarian carcinoma: a French multicenter study. Cancer 2001;91:2329–34. 25. Berek JS. Preoperative prediction of optimal resectability in advanced ovarian cancer using CA-125. Gynecol Oncol 2000; 77:225–6 [editorial].
www.ejso.com
A multicenter study of CA 125 level as a predictor of non-optimal primary cytoreduction of advanced epithelial ovarian cancer O. Gemera,*, M. Luriana, M. Gdalevichb, V. Kapustiana, E. Piurac, D. Schneiderd, O. Laviee, T. Levyf, A. Fishmang, R. Dganih, H. Levavii, U. Bellerj a
Department of Obstetrics and Gynecology Barzilai Medical Center, 78306 Ashkelon, Ben Gurion University of the Negev, Israel b District Health Office, Ashkelon, Israel c Soroka Medical Center, Beer Sheva, Israel d Assaf Harofe Medical Center, Tzrifin, Israel e Carmel Medical Center, Haifa, Israel f Wolfson Medical Center, Holon, Israel g Meir Medical Center, Kfar Saba, Israel h Kaplan Medical Center, Rehovot, Israel i Rabin Medical Center, Petah Tikva, Israel j Shaare Zedek Medical Center, Jerusalem, Israel Accepted for publication 18 May 2005 Available online 7 July 2005
KEYWORDS Epithelial ovarian cancer; CA 125; Cytoreduction; Prediction
Abstract Aims: To provide a large database of pre-operative CA 125 levels which may predict inappropriate cytoreductive surgery in patients with advanced epithelial ovarian cancer. Methods: A multicenter review of the records of 424 patients with FIGO stage III and IV epithelial ovarian cancer of patients who underwent primary cytoreductive surgery was performed. The validity of pre-operative CA 125 level measurement as a single predictor of the possibility to achieve only suboptimal cytoreduction was evaluated by calculating the sensitivity and the specificity of various cut-off values. The relative importance of different cut-off values in achieving the best predictive validity was assessed by a receiver operating characteristics (ROC) curve. Results: Optimal cytoreduction (largest diameter of residual tumour %1 cm) was achieved in 242 patients. The median CA 125 level in optimally cytoreduced patients was lower than in those patients suboptimally debulked (304 vs 863 U/mL; p!0.001). The area under the ROC curve was 0.65 (95% confidence interval, 0.60–0.71) and the
* Corresponding author. Tel.:C972 86745937; fax: C972 86745331. E-mail address: [email protected] (O. Gemer).
0748-7983/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2005.05.009
CA 125 level as a predictor of optimal cytoreduction
1007
CA 125 threshold derived from the ROC was 400 U/mL. The accuracy of the test at this level was 62%. Conclusions: The clinical applicability of the ROC derived CA 125 threshold is limited. The data accrued in the study provides a basis for decision-making regarding the place of primary surgery various CA 125 levels. Q 2005 Elsevier Ltd. All rights reserved.
Introduction The benefits of tumour cytoreduction in patients with advanced ovarian carcinoma are well recognized.1–4 Numerous studies, however, have demonstrated that tumour debulking improves survival only if optimal residual disease can be attained.3 As the reported optimal cytoreduction rates generally vary between 40–80%,5 the traditional approach of initial laparotomy does not benefit a significant proportion of the patients. On the other hand, withholding initial surgical attempt may deprive patients from a procedure that could substantially increase their survival.4 Women, in whom optimal cytoreduction is not attained, experience surgical morbidity without the compensatory survival advantage associated with an optimal result. As alternative treatment programs, such as neoadjuvant chemotherapy for patients with advanced disease at high risk for non-optimal debulking, are being studied,5–7 pre-operative criteria for predicting non-optimal cytoreduction are most valuable. In attempting to predict non-optimal cytoreduction two approaches have been advanced. A few studies relying on computerized tomography have defined radiological criteria which were found to be predictive of non-optimal debulking.8–11 In these studies various radiological features, or models in which they were accrued into an index, were able to predict the surgical outcome with an accuracy of 79–93%. However, the agreement between the reports, on predictive accuracy of the various radiological characteristics, was limited. The other approach has been to utilize the tumour marker CA 125 level which is known to correlate with tumour burden.12 While all studies of CA 125 levels were consistent in regard to the presence of a correlation between the tumour marker level and resectability, they differed in the threshold cut-off levels attained and their interpretation of the clinical utility.13–20 The CA 125 cut-off levels varied between 500 and 912 IU and the accuracy of the test at the threshold level ranged between 56 and 78%.13–20 These pre-operative CA 125 studies arrived at the threshold level utilizing a receiver operating curve (ROC) methodology. At the ROC
derived cut-off level which allowed equal weight for false-positive and false-negative outcome the clinical utility of the test is debatable. The purpose of this study is to provide a large multiinstitutional derived database for determining CA 125 levels which may predict unnecessary exploration rates in patients with advanced ovarian cancer.
Patients and methods A multicenter retrospective review of the records of 424 patients with International Federation of Gynecology and Obstetrics (FIGO) stage III and IV invasive epithelial ovarian cancer was made. Only patients who underwent an attempt at primary cytoreductive surgery were included. Data obtained from the charts included age, preoperative serum CA 125 levels, operative findings, procedure performed, residual disease at the end of the procedure and histology report. Optimal cytoreduction was defined in accordance with Gynecology Oncology Group (GOG) criteria when the diameter of the largest residual nodule measured less than or equal to 1 cm.2 The univariate analysis of the association between independent variables, such as age, tumour grade and histological type and the debulking result was performed by calculating the appropriate odds ratio (OR) and the corresponding 95% confidence interval (CI) for each. The comparison between CA 125 measurements in the two groups, according to the debulking result was done utilizing a Mann–Whitney U-test, a non-parametric approach, as the distribution of the measurements was substantially different from the normal distribution. The validity of pre-operative CA 125 level measurement as a predictor of suboptimal cytoreduction was evaluated by calculating the sensitivity and the specificity of various cut-off values. The sensitivity was defined as the percentage of patients with suboptimal cytoreduction, who had CA 125 level of above the given cut-off. Specificity was defined as the percentage of optimally
1008 Table 1
O. Gemer et al. Distribution of patients by age tumour histology, FIGO grade and debulking status
Age !60 R60 Histological type Papillary serous Mucinous Endometroid Other Grade 1 2 3
Suboptimal
Optimal
Total
Odds ratio (95% confidence interval)
61 121
119 123
180 244
Reference 1.92 (1.27–2.92)
136 7 12 25
195 7 18 21
331 14 30 46
Reference 1.43 (0.42–4.91) 0.96 (0.46–2.18) 1.71 (0.88–3.35)
8 24 140
18 35 173
26 59 313
Reference 1.54 (0.53–4.78) 1.82 (0.73–4.18)
cytoreduced patients who had CA 125 levels below the cut-off value.
ROC analysis The relative importance of different cut-off values in achieving the best predictive validity was assessed by constructing a receiver operating characteristics (ROC) curve, which plots the sensitivity on the y-axis and the false-positive rate (defined as 1-specificity) along the x-axis. The area under the ROC curve corresponds to the overall predictive validity. A value of 1 corresponds to a perfect accuracy measure and a value of 0.5 indicates pure chance. The point on the curve closest to the top left corner of the graph is the point where the sum of sensitivity and specificity is the highest. The closer this point is to the top left corner, the better the test (assuming false-negatives and false-positives are equally important). All computations were performed using the PEPI software for epidemiological analysis (Ver. 3, Stone Mountain, Georgia: USD Inc., 1999).
Results The median patient’s age was 62 years (range 25– 87). The median pre-operative serum CA 125 level was 495 U/mL (range 3–52,777), and it was elevated (O35 U/mL) in 392 patients. Twenty-five patients had stage III A disease, 75 had stage III B, 296 had stage III C and 28 had stage IV. Histologicaly, 331cases were papillary serous, 30 were endometroid 14 were mucinous and 46 had other histology. Twenty-six patients had grade 1 tumour, 59 had grade 2 and 313 had grade 3.
Optimal cytoreduction (largest diameter of residual tumour %1 cm) was reported in 242 patients. The distribution of patients by age, histological type, tumour grade and debulking status is shown in Table 1. A significantly greater proportion of patients younger than 60 were optimally debulked. The median CA 125 level in optimally cytoreduced patients was lower than in those patients debulked suboptimally (304 vs 863 U/mL, respectively; Mann–Whitney zZK5.51; p!0.001). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of performing non-optimal cytoreduction at various CA 125 threshold levels is shown in Table 2. Fig. 1 shows the ROC generated by the data; the area under the curve was 0.655 (95% confidence interval 0.603–0.708, p!0.0001) representing a significant difference from the hypothetical 458 ‘fifty-fifty’ Table 2 Prediction of suboptimal cytoreductive surgery at various CA 125 levels CA 125 cut-off level (U/ mL)
Sensitivity (%)
Specificity (%)
Positive predictive value
Negative predictive value
100 200 300 400 500 700 1000 1500 2500 5000 7500
89.0 80.2 74.7 69.2 63.2 53.3 45.1 30.8 18.1 5.5 3.8
26.4 38.8 49.6 57.0 61.6 66.1 75.2 84.7 90.5 97.5 97.9
47.6 51.8 52.7 54.8 55.3 54.2 57.7 60.2 58.9 62.5 58.3
76.2 74.6 72.3 71.1 69.0 65.3 64.5 61.9 59.5 57.8 57.5
CA 125 level as a predictor of optimal cytoreduction
Figure 1 Receiver operating characteristics curve (ROC) of correlation between sensitivity and falsepositive (1-specificity) rate for non-optimal cytoreductive surgery using each CA 125 level as a cut-off point.
line. The point on the curve closest to the upper left corner corresponds to a threshold level of 400 U/ mL. The accuracy of the test at this level was 62%.
Discussion This study corroborates the known relationship between CA 125 levels and outcome of cytoreductive surgery.13–20 As others,18 we found older age to be significantly associated with non-optimal debulking. A trend (not reaching statistical significance), associating non-optimal cytoreduction and higher tumour grade was noted. Statistically significant association of higher tumour grade and non-optimal debulking have been previously reported,18 as well as positive correlation between tumour grade and CA 125 levels.15,16 It is well recognized that the ability to perform optimal cytoreduction of advanced ovarian cancer reflects interplay between inherent biological features of the malignancy and surgical efforts.21 While optimal debulking rates of 98% have been reported,22 these rates which constitute the experience of a single center attest to a highly aggressive surgical attempt which may be associated with significant morbidity. Although the potential salutary value of neo-adjuvant chemotherapy in terms of survival benefit are still being studied,5 it has been appreciated that less radical surgery is needed for optimal cytoreduction if it follows chemotherapy.23,24,16 Under these circumstances, a triage mechanisms which will
1009 have wide applicability, and will allow a proportion of patients to be spared a futile surgery, yet compromise the benefits of primary surgery from relatively a small number of patients, seems reasonable. Some generalizations can be made on the studies utilizing CA 125 to predict non-optimal debulking.13–20 Most series report a median CA 125 of approximately 500 U/ml (the higher median CA 125 in some series may be a reflection of their being referral centers) and the optimal debulking rate in most centers ranges from 50 to 60%. The ROC derived CA 125 threshold level for non-optimal debulking in most series is also 500 U/mL; the area under the ROC ranging from 0.65 to 0.89. If this threshold level is used to select patients for surgery, approximately half of the patients will not be candidates for a primary surgical attempt. The limited usefulness of using pre-operative CA 125 for triage has been most stressed by two CA 125 studies,17,19 and by the work of Bristow et al.10 in which the pre-operative CA 125 level was not included among the radiological index parameters, because it was not sufficiently predictive of surgical outcome. This study by its size further confirms the limitation of the potential use ROC derived CA 125 cut-off level as a predictor of optimal surgery. Several authors have suggested that an appropriate CA 125 cut-off level would be between 1000 and 1500 U/mL.16,25 The data accrued this study may provide a basis for decision-making regarding the place of primary surgery at all CA 125 levels which may serve the expectations from primary cytoreductive surgery of both surgeon and the patient.
References 1. Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Elashoff RM. Primary cytoreductive surgery for epithelial ovarian cancer. Obstet Gynecol 1983;61:413–20. 2. Hoskins WJ, Bundy BN, Thigpen JT, Omura GA. The influence of cytoreductive surgery on recurrence-free interval and survival in small volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 1992;47: 159–66. 3. 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 1994;170:974–9. 4. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20:1248–59. 5. Van Der Burg ME, Vergote I, Gynecological Cancer Group of the EORTC. The role of interval debulking surgery in ovarian cancer. Curr Oncol Rep 2003;5:473–81.
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