Keywords: Epithelial ovarian cancer, normal CA125 levels, prognostic factors, survival
Published online 2015 January 29. doi: 10.5041/RMMJ.10180
The Significance of Normal Pretreatment Levels of CA125 (<35 U/mL) in Epithelial Ovarian Carcinoma
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, E. Wolfson Medical Center, Holon, Tel Aviv University, Sackler Faculty of Medicine, Tel Aviv, Israel
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Copyright: © 2015 Menczer et al.
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Objective:To assess the association between normal CA125 levels at diagnosis of epithelial ovarian carcinoma (EOC) with prognostic factors and with outcome.
Methods:The study group consisted of histologically confirmed EOC patients with normal pretreatment CA125 levels, and the controls consisted of EOC patients with elevated (≥35 U/mL) pretreatment CA125 levels, diagnosed and treated between 1995 and 2112. Study and control group patients fulfilled the following criteria: 1) their pretreatment CA125 levels were assessed; 2) they had full standard primary treatment, i.e. cytoreductive surgery and cisplatin-based chemotherapy; and 3) they were followed every 2–4 months during the first two years and every 4–6 months thereafter.
Results:Of 114 EOC patients who fulfilled the inclusion criteria, 22 (19.3%) had normal pretreatment CA125 levels. The control group consisted of the remaining 92 patients with ≥35 U/mL serum CA125 levels pretreatment. The proportion of patients with early-stage and low-grade disease, with optimal cytoreduction, and with platin-sensitive tumors was significantly higher in the study group than in the control group. The progression-free survival (PFS) and overall survival (OS) were significantly higher in the study group than in the control group on univariate analysis but not on multivariate analysis.
Conclusion:It seems that a normal CA125 level at diagnosis in EOC may also be of prognostic significance for the individual patient.
Keywords: Epithelial ovarian cancer, normal CA125 levels, prognostic factors, survival
Based on the initial report by Bast et al.,1 the serum level of 35 U/mL is considered as the cutoff point for CA125. The serum level of CA125 is widely used for distinguishing malignant from benign pelvic masses, for monitoring the response of epithelial ovarian cancer (EOC) to treatment, for follow-up, and for detecting disease recurrence. However, this marker has not proved a useful EOC screening test because of its low sensitivity and specificity.2,3 Thus, serum levels of CA125 may be in the normal range in 50% of symptomatic stage I patients and in about 10%– 20% of advanced-stage patients.3–5 Elevated CA125 levels are most common in patients with serous ovarian carcinoma (SOC), while the other types of EOC often present with normal serum CA125 levels.5
Current standard treatment for ovarian cancer consists of cytoreductive surgery, followed by platinum-taxane based combination chemotherapy.6 Well-known prognostic factors of EOC include stage, grade, and optimal surgical cytoreduction.7 The recent meaning of “optimal” cytoreduction connotes actually complete tumor resection, i.e. no gross residual tumor.8,9 The presence of platin sensitivity is also a prognostic factor.10 To stratify patients for optimal therapy, additional prognostic and predictive factors are needed.
The purpose of the present study was to assess the association between normal (<35 U/mL) pretreatment CA125 levels with prognostic factors and outcome in EOC patients.
The study group consisted of histologically confirmed EOC patients with normal pretreatment CA125 levels diagnosed and treated between 1995 and 2012. The controls consisted of EOC patients diagnosed during the same period with elevated (≥35 U/mL) pretreatment CA125 levels. The CA125 levels were tested in the same laboratory. Study and control group patients fulfilled the following inclusion criteria: 1) their pretreatment CA125 levels were assessed shortly before diagnosis and treatment; 2) they had full standard primary treatment; and 3) they were followed every 2–4 months during the first two years and every 4–6 months thereafter.
The records of the study and control group patients were retrospectively abstracted after institutional review board approval, and their clinicopathological data were recorded. All patients had primary cytoreductive surgery and surgical staging. Adjuvant chemotherapy consisted of intravenous paclitaxel (175 mg/m2) and carboplatin (AUC 6) for six 21-day cycles. Patients in whom recurrence occurred more than 6 months after completion of treatment were considered platin-sensitive.
Comparisons of the variables between patients with normal and elevated CA125 levels at diagnosis of EOC were made using the chi-square test for categorical variables and Fisher’s exact test, for small cells. Survival status was updated to September 2012. Overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan–Meier method, and comparison of survival between patients with normal and elevated CA125 was made by the log-rank test. Factors found to be significantly associated with survival on univariate analysis were evaluated using Cox proportional hazards regression testing.
During the study period 114 EOC patients who fulfilled the inclusion criteria were diagnosed. Among these, 22 (19.3%) patients had pretreatment CA125 levels within normal limits. They comprised 13 SOC and nine non-SOC patients. The latter consisted of five endometrioid and two each mucinous and clear cell tumors. The control group consisted of the remaining 92 patients with elevated serum CA125 levels. They comprised 69 SOC and 23 non-SOC patients. The latter consisted of 15 endometrioid, six mucinous, and two clear cell tumors. Adjuvant chemotherapy was given to 17 (77.3%) study group patients and to 89 (96.7%) controls. There was no statistically significant difference in the mean age between the study group and the control group (62.8±9.0 and 59.6±10.1 years, respectively). The mean CA125 level in the study group was 18.8±10.3 U/mL and that of the control group 1,357±1,100 U/mL. Additional selected characteristics of the study and control group patients according to CA125 level are presented in Table 1. The proportion of patients with stage I, grade 1, optimal cytoreduction, and platin-sensitive tumors was significantly higher in the study group than in the control group.
The median PFS in the study group was significantly higher than in the control group (90.2 and 22.7 months, respectively; P=0.016, HR 2.3, 95% CI 1.33–3.97) (Figure 1). The median OS in the study group was significantly higher than in the control group (not reached versus 78.1 months, respectively; P=0.033, HR 2.6, 95% CI 1.37–5.08) (Figure 2). On multivariate analysis only stage and grade were independent prognostic factors.
Our data indicate that normal pretreatment serum CA125 levels are associated with favorable prognostic factors and outcome in EOC patients.
Some issues concerning pretreatment CA125 are still controversial. In some studies it has been found that preoperative levels may reflect tumor burden,4,13 while others found no such correlation.14 In many studies it has also been shown that the preoperative level of CA125 can serve as a predictor of optimal tumor cytoreduction in advanced ovarian cancer.15–19 In these studies high preoperative CA125 serum levels were associated with decreased likelihood of achieving an optimal cytoreduction, although the threshold cutoff levels differed in them. On the other hand, in other studies preoperative serum CA125 level was not found to be a reliable predictor of optimal cytoreduction.20–25
Several studies included data regarding low preoperative CA125 levels (<100 U/mL) in the assessment of the ability to predict optimal cytoreduction and outcome. Vorgias et al.26 found that all of 19 patients with CA125 levels of <100 U/mL were optimally cytoreduced. Saygili et al.15 reported that at a serum level of <100 U/mL 80% of patients had optimal cytoreduction. According to Cooper et al.21 at the serum level of ≤61 U/mL the sensitivity and specificity for optimal cytoreduction were 15% and 98%, respectively, and the positive and negative predictive values were 93% and 37%, respectively. It was also reported that preoperative CA125 levels of <65 U/mL correlate with a better survival in EOC patients.27,28 In this context it is noteworthy that in patients with borderline ovarian tumors with CA125 levels lower than 50 U/mL the PFS and the OS were also found to be significantly better than in those with higher levels.29
We could locate only two studies that assessed specifically EOC patients with normal pretreatment CA125 levels. In a study that assessed only stage I patients, Paramasivam et al.11 found that the five-year overall survival rate was significantly higher for 176 patients with CA125 levels of <30 U/mL than in 342 patients with higher CA125 levels. Gundogdu et al.12 reported that significantly fewer stage III and IV patients with normal CA125 levels developed recurrence compared to those with higher levels.
We found that on univariate analysis normal pretreatment CA125 levels in EOC patients are significantly associated with lower stage and grade, with optimal cytoreduction, and with platin sensitivity. In view of the association between normal pretreatment serum CA125 levels with these favorable prognostic factors in our patients, the PFS and OS were also better than in those with elevated CA125 levels in univariate analysis. But, as could be expected, on multivariate analysis only stage and grade were independent prognostic factors. Nevertheless, it seems that a normal CA125 level at diagnosis of EOC is also of prognostic significance.
The main limitation of our study is the small number of EOC patients with normal CA125 levels pretreatment. Larger studies seem to be indicated.
Bast RC Jr, Klug TL, St John E, et al. A radio-immunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med. 1983;309:883–7. http://dx.doi.org/10.1056/NEJM198310133091503.
Duffy MJ, Bonfrer JM, Kulpa J, et al. CA125 in ovarian cancer: European Group on Tumor Markers guidelines for clinical use. Int J Gynecol Cancer. 2005;15:679–91. http://dx.doi.org/10.1111/j.1525-1438.2005.00130.x.
van Nagell JR Jr, Pavlik EJ. Ovarian cancer screening. Clin Obstet Gynecol. 2012;55:43–51. http://dx.doi.org/10.1097/GRF.0b013e3182460c0d.
Bast RC Jr, Urban N, Shridhar V, et al. Early detection of ovarian cancer: promise and reality. Cancer Treat Res. 2002;107:61–97.
Nossov V, Amneus M, Su F, et al. The early detection of ovarian cancer: from traditional methods to proteomics. Can we really do better than serum CA-125? Am J Obstet Gynecol. 2008;199:215–23. http://dx.doi.org/10.1016/j.ajog.2008.04.009.
Cannistra SA, Bast RC Jr, Berek JS, et al. Progress in the management of gynecologic cancer: consensus summary statement. J Clin Oncol. 2003;21:129s–32s. http://dx.doi.org/10.1200/JCO.2003.04.003.
du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer. 2009;115:1234–44. http://dx.doi.org/10.1002/cncr.24149.
Harter P, Hilpert F, Mahner S, et al. Prognostic factors for complete debulking in first- and second-line ovarian cancer. Int J Gynecol Cancer. 2009;19(Suppl 2):S14–17. http://dx.doi.org/10.1111/IGC.0b013e3181bffb3f.
Shih KK, Chi DS. Maximal cytoreductive effort in epithelial ovarian cancer surgery. J Gynecol Oncol. 2010;21:75–80. http://dx.doi.org/10.3802/jgo.2010.21.2.75.
Menczer J, Golan A, Levy T. Platin sensitivity and long-term survival in stage III epithelial ovarian cancer patients. Eur J Gynaecol Oncol. 2008;29:473–5.
Paramasivam S, Tripcony L, Crandon A, et al. Prognostic importance of preoperative CA-125 in International Federation of Gynecology and Obstetrics stage I epithelial ovarian cancer: an Australian multicenter study. J Clin Oncol. 2005;23:5938–42. http://dx.doi.org/10.1200/JCO.2005.08.151.
Gundogdu F, Soylu F, Erkan L, Tatli O, Mavi S, Yavuzcan A. The role of serum CA-125 levels and CA-125 tissue expression positivity in the prediction of the recurrence of stage III and IV epithelial ovarian tumors (CA 125 levels and tissue CA-125 in ovarian tumors). Arch Gynecol Obstet. 2011;283:1397–402. http://dx.doi.org/10.1007/s00404-010-1589-8.
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. 1996;41:140–2.
Kumar P, Rehani MM, Kumar L, et al. Tumor marker CA-125 as an evaluator and response indicator in ovarian cancer: its quantitative correlation with tumor volume. Med Sci Monit. 2005;11:CR84–9.
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;861:57–61. http://dx.doi.org/10.1006/gyno.2002.6719.
Gemer O, Lurian M, Gdalevich M, et al. A multicenter study of CA 125 level as a predictor of non-optimal primary cytoreduction of advanced epithelial ovarian cancer. Europ J Surg Oncol. 2005;319:1006–10. http://dx.doi.org/10.1016/j.ejso.2005.05.009.
Obeidat B, Latimer J, Crawford R. Can optimal primary cytoreduction be predicted in advanced stage epithelial ovarian cancer? Role of preoperative serum CA-125 level. Gynecol Obstet Invest. 2004;573:153–6. http://dx.doi.org/10.1159/000076236.
Mury D, Woelber L, Jung S, et al. Prognostic and predictive relevance of CA-125 at primary surgery of ovarian cancer. J Cancer Res Clin Oncol. 2011;1377:1131–7. http://dx.doi.org/10.1007/s00432-011-0977-1.
Brockbank EC, Ind TE, Barton DP, 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;141:42–50. http://dx.doi.org/10.1111/j.1048-891x.2004.14065.x.
Chi DS, Zivanovic O, Palayekar MJ, et al. A contemporary analysis of the ability of preoperative serum CA 125 to predict primary cytoreductive outcome in patients with advanced ovarian, tubal and peritoneal carcinoma. Gynecol Oncol. 2009;1121:6–10. http://dx.doi.org/10.1016/j.ygyno.2008.10.010.
Cooper BC, Sood AK, Davis CS, et al. Preoperative CA 125 levels: an independent prognostic factor for epithelial ovarian cancer. Obstet Gynecol. 2002;100:59–64. http://dx.doi.org/10.1016/S0029-7844(02)02057-4.
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;132:120–4. http://dx.doi.org/10.1046/j.1525-1438.2003.13019.x.
Alcázar JL, Miranda D, Unanue A, Novoa E, Alemán S, Madariaga L. CA-125 levels in predicting optimal cytoreductive surgery in patients with advanced epithelial ovarian carcinoma. Int J Gynaecol Obstet. 2004;842:173–4. http://dx.doi.org/10.1016/j.ijgo.2003.10.006.
Barlow TS, Przybylski M, Schilder JM, Moore DH, Look KY. The utility of presurgical CA125 to predict optimal tumor cytoreduction of epithelial ovarian cancer. Int J Gynecol Cancer. 2006;162:496–500. http://dx.doi.org/10.1111/j.1525-1438.2006.00573.x.
Kang S, Kim TJ, Nam BH, et al. Preoperative serum CA-125 levels and risk of suboptimal cytoreduction in ovarian cancer: a meta analysis. J Surg Oncol. 2010;1011:13–17. http://dx.doi.org/10.1002/jso.21398.
Vorgias G, Iavazzo C, Savvopoulos P, et al. Can the preoperative Ca-125 level predict optimal cytoreduction in patients with advanced ovarian carcinoma? A single institution cohort study. Gynecol Oncol. 2009;1121:11–15. http://dx.doi.org/10.1016/j.ygyno.2008.09.020.
Nagele F, Petru E, Medl M, Kainz C, Graf AH, Sevelda P. Preoperative CA 125: an independent prognostic factor in patients with stage I epithelial ovarian cancer. Obstet Gynecol. 1995;86:259–64. http://dx.doi.org/10.1016/0029-7844(95)00126-C.
Ind T, Iles R, Shepherd J, Chard T. Serum concentrations of cancer antigen CA125, placental alkaline phosphatase, cancer-associated serum antigen and free beta human chorionic gonadotrophin as prognostic markers for epithelial ovarian cancer. Br J Obstet Gynaecol. 1997;1049:1024–9. http://dx.doi.org/10.1111/j.1471-0528.1997.tb12061.x.
Tang A, Kondalsamy-Chennakesavan S, Ngan H, et al. Prognostic value of elevated preoperative serum serum CA125 in ovarian tumors of low malignant potential: a multinational collaborative study (ANZGOG0801). Gynecol Oncol. 2012;1261:36–40. http://dx.doi.org/10.1016/j.ygyno.2012.02.031.