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ORIGINAL RESEARCH |
From the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, and the Department of Biostatistics, Holden Comprehensive Cancer Center, the University of Iowa Hospitals and Clinics, Iowa City, Iowa.
Address reprint requests to: Anil K. Sood, MD, University of Iowa Hospitals and Clinics, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, 200 Hawkins Drive, Iowa City, IA 52242; E-mail: anil-sood{at}uiowa.edu.
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ABSTRACT |
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METHODS: One hundred forty-two patients with epithelial ovarian cancer, who had a serum CA 125 level drawn before surgery, were retrospectively evaluated. The relationship of preoperative CA 125 levels and various preoperative and postoperative variables was evaluated. CA 125 levels were determined using a solid-phase immunoassay.
RESULTS: The median CA 125 value for all patients was 582 U/mL (range 7–52,930 U/mL). Preoperative CA 125 values did not correlate with increasing age (P = .40), but were found to be significantly associated with serous histology compared with other histology (median CA 125 of 870 versus 334 U/mL, P = .02), high-stage (III/IV) compared with low-stage (median CA 125 of 893 versus 174 U/mL, P < .001), high tumor grade (3) compared with grade 1 or 2 (median CA 125 of 928 versus 323 U/mL, P < .001), and the presence of ascites compared with absence of ascites (median CA 125 of 893 versus 220 U/mL, P < .001). Suboptimal cytoreduction (more than 1 cm residual) was associated with significantly higher CA 125 levels (1067 U/mL) compared with individuals with optimal cytoreduction (399 U/mL, P < .001). Preoperative CA 125 values less than 500 U/mL had a positive predictive value for optimal cytoreduction of 82%, but a poor negative predictive value of 48%. After adjusting for covariates, there was a significant association between CA 125 levels and disease-specific survival. As preoperative CA 125 levels increased, the risk of death increased except at the highest values of CA 125.
CONCLUSION: Preoperative CA 125 is an independent risk factor for death due to disease in ovarian cancer, but not a reliable predictor of optimal cytoreduction.
Bast et al first described a radioimmunoassay that could detect CA 125 in the serum of ovarian cancer patients in 1983,1 but CA 125 is not useful as a screening test for ovarian cancer because up to 50% of patients with low-stage (I or II) cancer have normal levels.1–2 In addition, a variety of benign processes are associated with an elevated CA 125, especially in premenopausal women.1,3–9 The ability to monitor treatment and diagnose disease progression of ovarian cancer using CA 125 has been established,10 however, the clinical value of preoperative serum CA 125 levels in ovarian cancer remains to be defined. Several authors have studied preoperative CA 125 levels in evaluation of a pelvic mass.11–17 Preoperative CA 125 levels were helpful in diagnosing malignant masses in postmenopausal patients, but preoperative decisions regarding treatment could not be made on CA 125 levels alone because of the high false-positive rate of malignancy. There are limited data regarding the utility of CA 125 as a predictor of clinical or surgical outcome. Chi et al reported that in patients with a CA 125 level over 500 U/mL, only one in five could be optimally cytoreduced.18 However, this study was limited to stage III patients only. We undertook the present study to assess the usefulness of preoperative serum CA 125 levels in all patients with ovarian cancer with regard to prediction of clinical and surgical outcome.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients were evaluated for their preoperative CA 125 level, age, histology, grade, International Federation of Gynecologists and Obstetricians (FIGO) stage, presence or absence of ascites, residual disease, operative findings, timing of recurrence, and demise. Patients were followed for a minimum of 5 years. All patients underwent surgical exploration and cytoreduction as the initial treatment, performed by a staff gynecologic oncologist and a fellow. Optimal cytoreduction was defined as less than 1 cm residual disease (distinct nodules) after cytoreductive surgery, in accordance with studies published by the Gynecologic Oncology Group.19 All patients were surgically staged according to the FIGO staging system. The pathology for all patients was reviewed by a gynecologic pathologist. After surgery, all patients were treated with platinum and paclitaxel for adjuvant chemotherapy. The status of each patient was recorded as alive without disease, alive with disease, dead of disease, or dead of other causes.
The Wilcoxon-Mann-Whitney test and the Kruskal-Wallis test were used to compare the CA 125 distributions across subgroups of patients depending on age, histology, stage, grade, presence or absence of ascites, and cytoreduction. Survival analysis was based on death due to disease using the Cox proportional hazards regression model; P < .05 was considered significant. Patients who died of other causes or were alive at last follow-up were censored at the date of death or date of last follow-up.
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RESULTS |
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. The value of preoperative CA 125 ranged from 7 to 52,930 U/mL with a mean value of 2214 U/mL and a median of 582 U/mL. The mean value was greater than 75% of the observations. To evaluate the possible effect of age, patients were divided into four categories at the 25th, 50th, and 75th percentiles of distribution of age. There was no significant difference in preoperative CA 125 levels based on age (P = .40). This was also true when the patients were divided into two, three, and five equal-sized groups (P = .20, .74, and .85, respectively).
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Optimal surgical cytoreduction was achieved in 94 patients (66%). Patients who underwent optimal cytoreduction had a median preoperative CA 125 level of 399 U/mL. In contrast, for patients in whom optimal cytoreduction was not possible, the preoperative CA 125 was significantly higher (median = 1067 U/mL, P = .001). Among patients with stage III or IV disease, 65 of 112 (58%) underwent optimal surgical cytoreduction. Of this group, patients with optimal surgical cytoreduction had a median preoperative CA 125 of 715 U/mL, which was significantly lower than the 47 patients who underwent suboptimal cytoreduction (1095 U/mL, P = .03).
The sensitivity and specificity of preoperative CA 125 levels in predicting optimal cytoreduction was defined as percentage of optimally cytoreduced patients with CA 125 levels below a given cutoff (true-positive rate) and the percentage of suboptimally cytoreduced patients with a CA 125 level below that same cutoff, respectively. The results for all patients with cancer are shown in Table 2 and Figure 1. At a cutoff of 500 U/mL, 82% of patients with a lower CA 125 were optimally cytoreduced. Of those with a level higher than 500 U/mL, 52% were still able to undergo optimal surgical cytoreduction. Even among patients with a preoperative CA 125 level above 4450 U/mL (90th percentile), 40% underwent optimal surgical cytoreduction. When examining the ability of preoperative CA 125 levels to predict level of cytoreduction in advanced-stage patients only, a high positive predictive value is observed; but the negative predictive value remains low (Table 3).
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and Figure 2. Preoperative CA 125 levels have a high positive predictive value for predicting advanced stage at a given cutoff of CA 125, but a low negative predictive value.
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). The patients were divided into groups of equal numbers of patients with CA 125 levels of <160, 160–399, 400–924, 925–2399, and 2400+ U/mL. When the patients were divided into five equal groups, after adjusting for the six covariates in the multivariable analysis, the joint effect of preoperative CA 125 was significant for survival (P = .03). The hazard ratio of each group of patients increased compared with the group of patients with the lowest level of CA 125, but in a nonlinear fashion (Figure 3). The patients with the highest preoperative serum levels of CA 125 (>2400 U/mL) had a relatively low hazard ratio as compared with the patients with intermediate levels (925–2399 U/mL). When CA 125 was included in the multivariate model with the six covariates noted above, increasing age (P = .01), serous histology (P = .01), presence of ascites (P = .02), and CA 125 (P = .03) were independent predictors of poor outcome.
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DISCUSSION |
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Previous studies have shown that significant predictors of outcome in ovarian cancer patients include age, histologic subtype, grade, and volume of residual disease.29–32 Our study demonstrated a significant effect of increasing age, serous histology, high tumor grade, advanced stage, suboptimal cytoreduction, and presence of ascites on survival by univariate analysis. However, in the multivariate model, only increasing age, serous histology, presence of ascites, and CA 125 levels were significant. Advanced stage and high tumor grade were associated with a nonsignificant deleterious effect. Optimal cytoreduction was associated with better outcome, but this was not statistically significant. It is possible that with a larger cohort, level of cytoreduction and stage may be independent predictors of outcome. Most studies have not included preoperative CA 125 or presence of ascites in survival analyses,29–32 which may alter the significance of other covariates.
Preoperative CA 125 levels were previously shown to correlate with tumor stage and histologic grade.22,33–35 One study found a significant association of preoperative CA 125 levels with tumor stage and cytoreduction, but not histologic grade or type.20 Our data demonstrate a significant correlation of preoperative CA 125 levels with high stage, high tumor grade, histologic subtype, level of cytoreduction, and the presence of ascites, the latter of which has not been previously addressed.
Chi et al evaluated the ability of preoperative CA 125 levels to predict optimal cytoreduction in patients with stage III epithelial ovarian cancer.18 They found that at a cutoff of 500 U/mL, 73% of patients with a preoperative CA 125 level lower than this value underwent optimal cytoreduction, whereas only 22% of patients with a higher preoperative CA 125 level were optimally cytoreduced. In our study, 82% of all patients with preoperative CA 125 levels less than 500 U/mL underwent optimal cytoreduction, whereas 52% of patients with preoperative CA 125 levels above 500 U/mL were optimally cytoreduced. When examining only those patients who had stage III or IV cancer, we found that 74% of those with preoperative CA 125 levels less than 500 U/mL underwent optimal cytoreduction, whereas 51% of patients with levels above 500 U/mL were optimally cytoreduced. Thus, preoperative CA 125 does not appear to be a reliable predictor of optimal cytoreduction.
In summary, preoperative CA 125 levels correlate significantly with tumor stage, grade, histologic type, cytoreduction, and presence or absence of ascites, and are an independent prognostic factor in epithelial ovarian cancer.
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Footnotes |
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Received November 1, 2001. Received in revised form February 28, 2002. Accepted March 21, 2002.
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REFERENCES |
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