Abstract
Background
Our goal was to determine the prognostic significance of a pretreatment serum CA-125 level in advanced epithelial ovarian carcinoma (EOC) treated with a standard chemotherapy regimen.
Methods
FIGO stage III/IV patients on one of seven Gynecologic Oncology Group phase III trials who were treated with a standard regimen of intravenous cisplatin and paclitaxel were included. A Cox regression model was used to assess the impact of CA-125 levels drawn prior to chemotherapy initiation on progression-free survival (PFS) overall and by subgroups including surgical debulking status, stage, and histologic subtype.
Results
1,299 patients on the cisplatin/paclitaxel arm of the trials were eligible. The median CA-125 was 246 U/ml. Only 7.6% had a normal level (≤35 U/ml). The lowest median CA-125 was seen in the mucinous group, but 69% of mucinous tumors had an abnormal CA-125. Shorter PFS was seen with increasing CA-125 and persisted in multivariate analysis. Overall, as well as in the serous subgroup, a one-fold increase in CA-125 level was associated with a 7% increase in hazard for disease progression (p<0.001). This association was even more pronounced in stage III patients debulked to microscopic disease (15%, p=0.003) and in those with endometrioid tumors (17%, p=0.001).
Conclusions
A normal CA-125 level in the setting of advanced EOC is rare even after surgical debulking. Pretreatment CA-125 level is an independent predictor of PFS in advanced EOC treated with a standard chemotherapy regimen, particularly in the setting of disease debulked to a microscopic residual and the serous or endometrioid subtypes.
INTRODUCTION
CA-125 is the serum tumor marker most closely associated with epithelial ovarian cancer (EOC). Originally described by Bast et al. in 1981, it is an antigenic determinant on a high molecular weight glycoprotein recently described as MUC16 and recognized by the murine monoclonal antibody OC-125 (1,2). In subsequent studies, CA-125 values >35 U/ml were documented in 80–85% of women found to have ovarian cancer (3,4). For women with advanced disease, the rate of elevated CA-125 is even higher at >90% (4).
The prognostic significance of CA-125 is well recognized in EOC, but most of the patients studied to date have had tumors with serous histology. The prognostic value of CA-125 for the other histologic subtypes of EOC has not been well documented, especially when stage and surgical debulking status are taken into consideration. In addition, the prognostic significance of a normal CA-125 in the setting of advanced EOC has not been evaluated. Some of the difficulty arises from the lack of understanding of why some tumors are associated with an elevated CA-125 while others are not. The most commonly cited reason for a normal CA-125 is the mucinous histologic subtype; however, 69% of these tumors have been associated with abnormal CA-125 values (4).
The objective of this study was to evaluate whether the pretreatment CA-125 level can be used to predict disease progression in advanced EOC, particularly when stage, debulking status, and histologic subtype are taken into consideration. Conducted as an ancillary data project of the Gynecologic Oncology Group (GOG), the study incorporated patients from seven closed GOG Phase III protocols that utilized a standard regimen of intravenous cisplatin and paclitaxel in one treatment arm.
METHODS
A retrospective review of data from seven prospective, randomized clinical trials conducted by the GOG, including protocols 111, 114, 132, 152, 158, 162, and 172, was performed. Patients included in this analysis were treated with primary surgical cytoreduction followed by six cycles of intravenous paclitaxel 135 mg/m2 over 24 hours and cisplatin 75 mg/m2. Although patients on the experimental arm of GOG 152 received the same chemotherapy regimen divided before and after secondary cytoreductive surgery, they were excluded in an attempt to maintain the most consistent treatment possible. Likewise, the patients on GOG 162 who received the 96-hour paclitaxel regimen were also excluded. For information on patient eligibility, treatment and clinical outcomes, please refer to previous publications (5–11).
CA-125 collection after surgery but prior to chemotherapy initiation was requested in all of the protocols. Demographic information, stage, debulking status (optimal with microscopic residual disease, optimal with gross residual disease, or suboptimal), tumor grade, and histologic subtype were evaluated. The associations between CA-125 and these clinical characteristics were assessed by analysis of variance (ANOVA), where CA-125 values were transformed to a logarithm scale.
The endpoint of the study was progression-free survival (PFS), defined as the time interval from study entry to disease recurrence or death. PFS by CA-125 stratum was estimated by the Kaplan-Meier procedure. CA-125 was divided into six categories: ≤35, 36–100, 101–200, 201–500, 501–1000 and >1000 U/ml. This classification took into account the most common definition of a normal CA-125 level (≤35 U/ml) and allowed a comparable number of patients in each category. The relative risk for disease progression was estimated using a Cox model adjusted for age, performance status, stage/debulking status, histology, and tumor grade. CA-125 was analyzed as either a categorical or continuous variable. When analyzed as a categorical variable, the relative risk was reported as compared to the normal group (CA-125 ≤35 U/ml); when analyzed as a continuous variable, the relative risk was reported for a one-unit increase in Log2(CA-125), which can be interpreted as the relative risk with a one-fold increase in the raw CA-125 level. The linearship between Log2 (CA-125) and risk of disease progression was assessed using the graphic method suggested by Hosmer and Lemeshow (12). Briefly, the patients were divided into ten groups based on CA-125, with each group having an equal number of patients. Design variables were created for each group and included into the Cox model. The regression coefficients against the group midpoints were graphed using a smoothing manner. Subgroup analysis by stage/debulking status (stage III-optimal with microscopic residual disease, stage III-optimal with gross residual disease, stage III-suboptimal, and stage IV) and by histologic subtype (serous, endometrioid, mucinous, clear cell, and other) was performed using the same method where CA-125 was analyzed as continuous variable. All statistical analyses were performed on SAS version 9.1 with p-values reported as two-sided.
RESULTS
From a total of 1,570 patients treated on the cisplatin/paclitaxel arm of the seven GOG protocols, 1,299 (83%) had pretreatment CA-125 values available and were included in this analysis (Table 1). The exact timing of the postoperative CA-125 value (i.e. which postoperative day) was not specified. Nine were obtained preoperatively with no repeat value reported after surgery but before chemotherapy. These values were all <35 U/ml and were included in the analysis since they represented pretreatment values that were already normal before surgery.
TABLE 1.
GOG PROTOCOLS AND STUDY POPULATIONS
| GOG Protocol | Patient population | Total patients on cisplatin 75 mg/m2 plus paclitaxel 135 mg/m2 over 24 hours arm | Patients with pretreatment CA-125 (%) |
|---|---|---|---|
| 111 | Suboptimal Stage III/IV | 184 | 163 (89) |
| 114 | Optimal Stage III | 226 | 179 (79) |
| 132 | Suboptimal Stage III/IV | 201 | 181 (90) |
| 152 | Suboptimal Stage III/IV | 209 | 169 (81) |
| 158 | Optimal Stage III | 400 | 343 (86) |
| 162 | Suboptimal Stage III/IV | 140 | 94 (67) |
| 172 | Optimal Stage III | 210 | 170 (81) |
|
| |||
| Total | 1570 | 1299 (83) | |
Suboptimal disease defined as residual > 1cm for all studies except GOG 162 where defined as > 1cm retroperitoneal disease or ≤1 cm intraperitoneal disease. Optimal disease defined as residual ≤1cm for all studies. Patients with no pretreatment CA-125 available, who underwent interval debulking (GOG 152), who were treated with a 96-hr infusion (GOG 162), or who received intraperitoneal treatment (GOG 172) were not included. See references 4–10.
The median pretreatment CA-125 level was 246 U/ml, while only 99 patients (7.6%) had a normal level (≤35 U/ml). The characteristics of these 99 patients are summarized in Table 2. Seventy-nine patients had ≤1 cm residual disease after debulking surgery, while 20 were suboptimally debulked or had Stage IV disease. The majority of the patients with a normal pretreatment CA-125 had serous histology (64.6%), but among the histologic subtypes, mucinous had the largest percentage with a normal pretreatment CA-125 (30.8%). Mucinous tumors had a median pretreatment CA-125 value of 99 U/ml, the lowest among the histologic subtypes but still in the abnormal range (Table 3).
TABLE 2.
CHARACTERISTICS OF PATIENTS WITH NORMAL PRETREATMENT CA-125
| Distribution of 99 Patients with Normal Pretreatment CA-125 | Percentage of Patients in Each Subgroup with Normal Pretreatment CA-125 | |
|---|---|---|
| Stage | ||
| III- optimal microscopic | 40.4% | 16.0% |
| III- optimal gross | 39.3% | 8.8% |
| III- suboptimal | 15.2% | 3.6% |
| IV | 5.1% | 2.7% |
| Histologic Subtype | ||
| Serous | 64.6% | 6.8% |
| Endometrioid | 6.1% | 5.2% |
| Mucinous | 8.1% | 30.8% |
| Clear Cell | 3.0% | 8.1% |
| Other | 18.2% | 9.8% |
TABLE 3.
PATIENT CHARACTERISTICS AND PRETREATMENT CA-125 LEVELS
| Characteristic | No. | CA-125 (U/ml) Median (25th –75th Pct) | Log2(CA-125) Mean (SD) | P value1 |
|---|---|---|---|---|
| Age (years) | 0.02 | |||
| ≤ 50 | 365 | 202 (85–598) | 7.85 (2.11) | |
| 51–60 | 370 | 278 (118–903) | 8.35 (2.25) | |
| 61–70 | 382 | 256 (113–722) | 8.19 (2.13) | |
| > 70 | 182 | 224 (105–667) | 8.07 (2.12) | |
| Race | 0.17 | |||
| White | 1157 | 251 (103–740) | 8.15 (2.14) | |
| Black | 74 | 142 (60–576) | 7.66 (2.56) | |
| Other | 68 | 239 (151–761) | 8.12 (2.09) | |
| Performance | <0.001 | |||
| 0 | 509 | 203 (84–601) | 7.86 (2.16) | |
| 1 | 650 | 258 (112–840) | 8.23 (2.14) | |
| 2 | 140 | 356 (150–840) | 8.58 (2.22) | |
| Stage | <0.001 | |||
| III-optimal micro | 250 | 117 (54–221) | 6.86 (1.78) | |
| III-optimal gross | 442 | 203 (86–485) | 7.77 (1.91) | |
| III-suboptimal | 420 | 407 (170–1393) | 8.85 (2.21) | |
| IV | 187 | 443 (170–1427) | 9.01 (2.10) | |
| Histology | 0.007 | |||
| Serous | 936 | 256 (103–759) | 8.17 (2.15) | |
| Endometrioid | 117 | 239 (114–561) | 8.12 (2.08) | |
| Mucinous | 26 | 99 (26–336) | 6.81 (2.38) | |
| Clear cell | 37 | 154 (87–390) | 7.43 (1.74) | |
| Other | 183 | 247 (102–840) | 8.22 (2.23) | |
| Tumor Grade | <0.001 | |||
| 1 | 115 | 120 (55–430) | 7.19 (2.04) | |
| 2 | 489 | 227 (96–723) | 8.08 (2.21) | |
| 3 | 658 | 296 (117–838) | 8.35 (2.12) | |
| Clear cell | 37 | 154 (87–390) | 7.43 (1.74) | |
| Total | 1299 | 246 (101–741) | 8.12 (2.17) |
Reported from ANOVA based on Log2 (CA-125).
CA-125 levels differed significantly by age group, performance status, stage/debulking status, histology and tumor grade (Table 3). A lower pretreatment CA-125 was associated with age ≤50 years and normal performance status (GOG performance status 0).
With a median follow-up period of 39 months for all patients, 1,132 patients (87.1%) showed disease progression (either disease recurrence or death). With CA-125 stratified into six categories, Kaplan-Meier survival estimates reveal an association of shorter PFS with increasing pretreatment CA-125 except for comparable PFS in the 200–500 and 500–1,000 U/ml strata (Figure 1). Using the ≤35 stratum as the referent, the association of pretreatment CA-125 level with disease progression was evaluated in a Cox model. Hazard ratios were adjusted for age, performance status, stage/debulking status, histology, and tumor grade (Figure 2A). As pretreatment CA-125 increases, the risk for disease progression also increases, until at levels >1,000 there is a 71% increase in risk of disease progression compared to a normal level. When CA-125 was analyzed as a continuous variable, the logarithm scale of hazard ratio was approximately linear to the logarithm scale of pretreatment CA-125 (Figure 2B), with an 11% increase for each doubling of the pretreatment CA-125 level (HR: 1.11, 95% CI: 1.08–1.14, p<0.001). When adjusted for covariates, the increased risk of disease progression was 7% for each doubling of the pretreatment CA-125 level (HR: 1.07, 95% CI: 1.04–1.10, p<0.001). A similar analysis of the relationship between pretreatment CA-125 and overall survival also showed a significant association (data not shown).
FIGURE 1.
Estimate for Progression-free Survival by CA-125 Level
FIGURE 2.
ASSOCIATION OF PRETREATMENT CA-125 LEVEL WITH DISEASE PROGRESSION
Cox modeling identified an interactive effect between pretreatment CA-125 and stage/debulking status on the risk of disease progression (test for interaction: p=0.03). Further analyses were conducted to assess the association between pretreatment CA-125 and PFS for each subgroup. Figure 3A shows the adjusted risk of disease progression with a one-fold increase in pretreatment CA-125 according to stage/debulking status. The extent of association decreased moving from patients with stage III/less residual disease to stage IV patients. For example, a one-fold increase in pretreatment CA-125 level was associated with a 15% increase in risk of disease progression for stage III/optimal-microscopic patients (HR: 1.15, 95% CI: 1.05–1.26, p=0.003), while the increased risk was only 6% for stage IV patients (HR: 1.06, 95% CI: 0.99–1.14, p=0.10).
FIGURE 3.
FIGURE 3A. ASSOCIATION OF PRETREATMENT CA-125 WITH DISEASE PROGRESSION BY STAGE/SURGICAL DEBULKING STATUS
Adjusted hazard ratio reported as one-fold increase in pretreatment CA-125 level. Stage/debulking status reported for Stage III disease optimally debulked to a microscopic residual, Stage III disease optimally debulked to ≤1 cm residual, Stage III disease suboptimally debulked, and Stage IV disease.
FIGURE 3B. ASSOCIATION OF PRETREATMENT CA-125 WITH DISEASE PROGRESSION BY HISTOLOGIC SUBTYPE
Adjusted hazard ratio reported as one-fold increase in pretreatment CA-125 level.
No statistically significant interaction between pretreatment CA-125 and histologic subtype was identified overall (p=0.241). However, the adjusted risk for disease progression with a one-fold increase in pretreatment CA-125 depicted in Figure 3B shows that the association was more evident for the endometrioid subtype (HR: 1.17, 95%CI: 1.06–1.28, p=0.001) than the serous subtype (HR: 1.07, 95% CI: 1.04–1.11, p<0.001). The correlation between pretreatment CA-125 and risk for disease progression for mucinous and clear cell subtypes was not statistically significant, likely due to small sample sizes for those two groups.
DISCUSSION
This large cohort of women with advanced EOC was treated on randomized cooperative group protocols with a consistent chemotherapy regimen undergoing centralized data review. The primary limitation of the study is the retrospective nature of the data collection. The timing of CA-125 collection was not specified by the protocols, leading to a mix of specimens collected preoperatively, immediately postoperatively, or further into the postoperative course but before chemotherapy was started. CA-125 levels were recorded as raw values without the local laboratory reference range. The upper limit of normal on current assays ranges from 21 to 40 U/ml. For purposes of this analysis, the commonly accepted definition of normal CA-125 ≤35 U/ml was employed. The analysis was also limited by the use of single rather than repeated pretreatment values. Because of the lack of paired preoperative and postoperative CA-125 values, the immediate impact of surgery and debulking on pretreatment CA-125 values could not be assessed. Previous research suggests that surgical trauma may temporarily elevate the CA-125 level in patients with benign disease and a previously normal level, while debulking ovarian cancer generally leads to a decrease in an elevated CA-125 level (13). An additional limitation is the small number of mucinous and clear cell tumors included. Despite its multi-institutional nature, this analysis only included 26 patients with mucinous EOC and 37 with clear cell EOC, emphasizing the difficulty of studying the rare histologic subtypes even in a cooperative group setting.
Although CA-125 is generally thought to remain normal in 15–20% of EOC, that rate drops to <10% when advanced stage disease is considered (4). A recent analysis of data from a Southwest Oncology Group trial showed that seven out of 101 patients (6.9%) with suboptimally debulked advanced EOC had a pretreatment CA-125 value ≤35 U/ml (14). Similarly, in the current analysis with a mix of optimally and suboptimally debulked patients, only 7.6% of patients were noted to have a pretreatment CA-125 ≤35 U/ml, confirming the original studies from the 1980s.
In addition, these data suggest that histology and resectability alone do not explain the absence of CA-125 elevation in the setting of advanced EOC. Specifically, although the mucinous group had the highest percentage of patients with a CA-125 ≤35 U/ml among the histologic subtypes (30.8%), patients with mucinous tumors accounted for only 8.1% of all the normal CA-125 patients. Further, 20.3% of patients with a normal CA-125 had suboptimally debulked Stage III or Stage IV disease.
A recent GOG analysis that included patients from six of the studies also included in this study found that age, performance status, tumor residual after debulking surgery, and tumor histology were independent prognostic factors for stage III EOC (15). Our regression analysis included clinical factors such as patient age, performance status, stage/debulking status, histology and tumor grade to control for their impact on the association of CA-125 level with outcome. In general, the clinical factors may contribute more to outcome, making the CA-125 level contribute comparatively less. However, in subgroup analyses where the most important clinical factors such as tumor residual or histology are controlled, the relative prognostic value of CA-125 level is more apparent among patients with favorable clinical factors. This may help explain the higher significance of the pretreatment CA-125 association with PFS in the microscopic residual, serous histology, and endometrioid histology groups, since these groups usually have a better prognosis than women with stage IV disease, suboptimal debulking, or unfavorable clear cell or mucinous histology. Extending the evaluation of pretreatment CA-125 to early stage ovarian cancer would add to the recent analysis of prognostic factors in this group; as a population with an even more favorable prognosis than stage III patients with microscopic residual and serous or endometrioid histology, CA-125 may be a significant independent predictor of outcome (16).
Although many clinical studies have concentrated on the use of serial measurements of CA-125 during chemotherapy for prognosis, the pretreatment CA-125 level remains of interest since it has the potential to predict prognosis even before the start of chemotherapy when used together with other clinical factors. In addition to stage, tumor residual, histologic subtype, tumor grade, age, and performance status, this analysis suggests that pretreatment CA-125 can be considered a prognostic factor in EOC. The use of a large population that was treated similarly makes the estimate of relative risk more accurate. After adjusting for covariates, we found that a one-fold increase in pretreatment CA-125 level was associated with a 7% increase in the risk for progression of advanced EOC. Knowledge of poor prognostic factors at the start of chemotherapy may help clinicians and patients prioritize participation in protocol therapy investigating novel agents in the treatment of epithelial ovarian cancer.
Acknowledgments
This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517).
The authors would like to thank Dr. M.J. Krohn who assisted with the development of the initial concept for this project.
Footnotes
All authors meet the three criteria for authorship, and each certifies that the manuscript represents valid work and has not been previously published nor is under consideration for publication elsewhere.
Abbreviated results of this study were presented in abstract form at the SGO Annual Meeting in 2007.
The following Gynecologic Oncology Group member institutions participated in the primary treatment studies: University of Alabama at Birmingham, Oregon Health Sciences University, Duke University Medical Center, Abington Memorial Hospital, University of Rochester Medical Center, Walter Reed Medical Center, Wayne State University, University of Minnesota Medical School, University of Southern California at Los Angeles, University of Mississippi Medical Center, Colorado Gynecologic Oncology Group, P.C., University of California at Los Angeles, University of Miami School of Medicine, Milton S. Hershey Medical Center, Georgetown University Hospital, University of Cincinnati, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, Indiana University Medical Center, Wake Forest University School of Medicine, Albany Medical Center, University of California Medical Center at Irvine, Tufts-New England Medical Center, Rush-Presbyterian-St. Luke’s Medical Center, Stanford University Medical Center, SUNY Downstate Medical Center, University of Kentucky, Eastern Virginia Medical School, The Cleveland Clinic Foundation, Johns Hopkins Cancer Center, State University of New York at Stony Brook, Eastern Pennsylvania Gynecology/Oncology Center, P.C., Washington University School of Medicine, Cooper Hospital/University Medical Center, Columbus Cancer Council, M. D. Anderson Cancer Center, University of Massachusetts Medical School, Fox Chase Cancer Center, Medical University of South Carolina, Women’s Cancer Center, University of Oklahoma.
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