Abstract
Background/Aim: To analyze the relationship between clinical outcomes for epithelial ovarian cancer and serum CA-125 levels after chemotherapy in Korean women. Patients and Methods: This study included 183 patients who underwent the standard treatment regimen for epithelial ovarian cancer. They were divided into early- (I, II) and advanced-stage (III, IV) groups. Serum CA-125 level after adjuvant chemotherapy completion (post-chemotherapy; PC-CA-125) was measured. Overall survival (OS), progression-free survival (PFS), platinum-free interval (PFI), and platinum resistance were evaluated. Results: In advanced-stage group, OS, PFS, PFI, and platinum resistance were significantly correlated with PC-CA-125. In early-stage group, PFS and platinum resistance differed significantly. Cutoff value for platinum resistance was 10.45 U/ml, 10.40 U/ml, and 15.80 U/ml for study population, early stage, and advanced groups, respectively. Accuracy was 71.1%-77.1%. Conclusion: PC-CA-125 is correlated with clinical outcomes in ovarian cancer. Thus, CA-125 can be used to predict platinum resistance in ovarian cancer treatment.
- Ovarian cancer
- chemotherapy
- clinical outcomes
- overall survival
- progression-free survival
- platinum-free interval
- platinum resistance
- CA-125
Cancer antigen 125 (CA-125) is a tumor marker that has been used for monitoring ovarian cancer worldwide in the last two decades (1, 2). Although not increased in some histologic subtypes of ovarian cancer, it still has diagnostic value in combination with other complementary serum markers (3, 4). Additionally, as a tumor marker itself, CA-125 has recently been correlated with clinical outcomes in ovarian cancer in numerous studies (5-8).
After the concept of platinum resistance had been introduced, many researchers subsequently focused on its management. When platinum resistance occurs, the disease progresses faster, and the response to subsequent treatment is poorer (9, 10). Although the mechanisms and biomarkers of ovarian cancer have been revealed, its prognosis has not improved significantly (11, 12).
Trials on CA-125 and platinum resistance have been conducted to identify their correlations with each other, and some have reported it to a limited extent (13, 14). Especially according to the report of Jung et al., CA-125 tends to decrease in a high proportion of patients with a CA-125 level below 10 U/ml after six cycles of chemotherapy (14). We sought to determine whether this tendency could have statistical significance.
Patients and Methods
Patients. We enrolled 271 patients who underwent debulking surgery for ovarian tumor from February 2011 to January 2021 at Kyungpook National University Chilgok Hospital (KNUCH) and retrospectively reviewed their medical records. Forty-four participants were excluded because they were not diagnosed with primary ovarian cancer on biopsy. Additionally, 6 patients whose histologic subtypes were not epithelial and 11 who refused adjuvant chemotherapy after debulking surgery were also excluded. Further, 13 cases with missing information on serum CA-125 levels after chemotherapy and 14 cases that did not complete at least 4 cycles of adjuvant chemotherapy were excluded. A total of 183 participants were included in this study (Figure 1). The cancer stage of each patient was evaluated using the International Federation of Gynecology and Obstetrics staging criteria (15). Patients with Stage I or II were grouped as early stage, whereas those with Stage III or IV comprised the advanced-stage group. The Institutional Review Board of KNUCH approved this study (KNUCH 2021-09-007).
Flow diagram for patient selection. *1Included benign, borderline, and other primary malignancies, such as endometrial cancer or colon cancer; *2Included germ cell tumor, sex cord stromal tumor, and other subtypes.
Surgery. Surgeries performed included total abdominal hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic lymphadenectomy, para-aortic lymphadenectomy, omentectomy, and removal of metastatic lesions. Some participants were treated with interval debulking surgery (IDS) after neoadjuvant chemotherapy for their clinical condition. Optimal surgery was defined as surgery performed when the residual tumor size was <1 cm (16).
Chemotherapy. The chemotherapy regimen administered was mostly a combination of taxane and carboplatin. All patients finished at least four cycles of adjuvant chemotherapy (17).
Platinum resistance. We evaluated platinum resistance based on recurrence or disease progression that occurred within 6 months after the last administration of platinum-based therapy (9), which was confirmed by either computed tomography (CT) or magnetic resonance imaging or positron emission tomography/CT (18).
Measurement of serum CA-125. Serum CA-125 level was measured at least thrice within the follow-up period. Preoperative CA-125 was measured before debulking surgery. For patients who underwent IDS, the preoperative CA-125 was measured after the completion of neoadjuvant chemotherapy before surgery. Postoperative CA-125 was measured after the surgery and before the first administration of antitumor agents. Post-chemotherapy CA-125 (PC-CA-125) was measured within 4 weeks after six cycles of chemotherapy, including for patients who underwent 4-5 cycles.
Statistical analysis. Student’s t-test was used to compare the mean values between the early- and advanced-stage groups. To analyze the relationship between certain factors in the two groups, the chi-square or Fisher’s exact test was used. The receiver operating characteristic (ROC) curve was applied, and the area under curve (AUC) was evaluated. Youden’s index was used to determine the cutoff values. All statistical analyses were performed using SPSS (version 26; IBM Corp., Armonk, NY, USA).
Results
Out of 183 patients, 48 (26.2%) were classified into the early-stage group, whereas 135 (73.8%) were classified into the advanced-stage group. Clinical factors, including age, residual tumor, and first chemotherapy regimen, were not statistically significant. Endometrioid and clear cell histological subtypes and primary debulking surgery were significantly more common in the early-stage group. Preoperative and post-chemotherapy serum CA-125 levels were significantly lower in the early stage but did not significantly differ from the postoperative levels (Table I).
Comparison of patients’ characteristics and clinical factors.
In the comparison of clinical outcomes between both groups, the number of deaths in the early-stage group within the follow-up period was 0, whereas it was 27 in the advanced-stage group (20.0%). Platinum resistance occurred in 4 (8.3%) cases in the early stage and 21 (15.6%) cases in the advanced stage. Platinum resistance varied significantly between both groups (p<0.01). The mean±standard deviation of overall survival (OS) in the early-stage group was 58.17±22.40 months and 53.39±23.63 months in the advanced-stage group, but no significant difference was observed (p=0.22). The mean progression-free survival (PFS) in the early-stage group was 49.73±23.10 months and 31.16±20.92 months in the advanced-stage group but was significantly longer in the early-stage group (p<0.01). The mean platinum-free interval (PFI) in the early-stage group was 21.75±19.62 months and 15.60±13.32 months in the advanced-stage group, but the difference between the two groups was not significant (p=0.31). For the 5-year response to treatment, complete resolution (CR) was achieved in 36 (75.0%) cases in the early-stage group and 45 (33.3%) cases in the advanced-stage group. The number of recurrences was 12 (25.0%) cases in the early-stage group and 90 (66.7%) cases in the advanced-stage group, and the difference between the two groups was significant (p<0.01) (Table II).
Comparison of clinical outcomes.
We analyzed the relationships of PC-CA-125 with clinical outcomes, such as OS, PFS, and PFI, using linear regression analysis. Multivariate analysis also included preoperative and postoperative serum CA-125 levels and showed significant relationships between PC-CA-125 and OS, PFS, and PFI in the total study population (p=0.01, p<0.01, and p=0.02, respectively). The results were the same in the univariate analysis of PC-CA-125 for the total study population (p=0.01, p<0.01, and p=0.01, respectively). In multivariate analysis for the early-stage group, PC-CA-125 was significantly correlated with PFS alone (p=0.03 and p=0.01, respectively). In multivariate analysis for the advanced-stage group, significant relationships between PC-CA-125 and OS, PFS, and PFI were observed (p=0.02, p<0.01, and p=0.02, respectively). These relationships were also significant on univariate analysis (p=0.02, p<0.01, and p=0.01). We conducted logistic regression analysis to assess the relationship between PC-CA-125 and platinum resistance. In both multivariate (p=0.01) and univariate (p<0.01) analyses of preoperative and postoperative CA-125 and PC-CA-125, a significant relationship was found between platinum resistance and PC-CA-125 in the total study population. In multivariate and univariate analyses for the early-stage (p=0.03 and p=0.02, respectively) and advanced-stage (p=0.03 and p=0.02, respectively) groups, PC-CA-125 was significantly correlated with platinum resistance (Table III).
Regression analysis between post-chemotherapy CA-125* levels and clinical outcomes.
We analyzed the ROC curve to determine the cutoff value of PC-CA-125 for platinum resistance in the total population and early-stage and advanced-stage groups. Statistical significance was observed in all three groups (p<0.01, p=0.01, and p<0.01, respectively). The AUC of each was 0.765, 0.881, and 0.732, respectively. The cutoff value was 10.45 U/ml for the total population, 10.40 U/ml for the early-stage group, and 15.80 U/ml for the advanced-stage group (Figure 2). The sensitivity in each group was 84.0%, 100%, and 71.4%, respectively, whereas the specificity was 64.6%, 75.0%, and 71.1%, respectively. The negative predictive value was 96.2%, 100%, and 93.1%, respectively, whereas the positive predictive value was 27.3%, 26.7%, and 31.3%, respectively. Furthermore, the accuracy was 72.7%, 77.7%, and 71.1%, respectively.
Receiver operating characteristic curves of the relationship between post-chemotherapy CA-125 levels and platinum resistance for A) the total study population, B) early-stage group, and C) advanced-stage group.1
Discussion
In this study, we showed that PC-CA-125 is significantly correlated with OS, PFS, PFI, and platinum resistance. We also successfully determined the cutoff PC-CA-125 values for early- and advanced-stage ovarian cancer to predict platinum resistance.
Serum CA-125 is relatively easy and inexpensive to measure. Many gynecologic oncologists use serum CA-125 levels to monitor the prognosis of ovarian cancer. We recommend its measurement after 4-6 cycles of first-line chemotherapy. It is not only easy, safe, and inexpensive but also very useful to predict the prognosis. Its comparable accuracy in predicting platinum resistance can help physicians create a surveillance plan for the disease.
A similar study had evaluated the correlation between clinical outcomes in ovarian cancer and serum CA-125 level after chemotherapy (19). In our study, the prognostic ability of CA-125 after chemotherapy was reaffirmed both in the early and advanced stages. A previous study for ovarian clear cell carcinoma found that 66.4 U/ml of CA-125 right after debulking surgery was the cutoff value for platinum resistance (13). In our study, postoperative CA-125 did not significantly predict platinum resistance upon ROC curve analysis (p=0.17). Although the preoperative CA-125 and PC-CA-125 were significantly lower in the early stages than advanced stages, the postoperative level did not differ significantly in this study. We found 48 cases of paradoxically increased CA-125 levels after surgery in the total population, 18 (34.0%) in the early stage and 30 (20.8%) in the advanced stage. Although not significant on the chi-square test (p=0.06), this might have led to the non-significant prognostic ability of postoperative CA-125. This phenomenon was also reported in another study (20). Because of failure to evaluate cutoff values and the paradoxical increase, we consider PC-CA-125 to be a more valuable predictor than postoperative CA-125.
Studies on neoadjuvant chemotherapy (7, 8) have shown clinical value of the serum CA-125 for the prediction of prognostic outcomes after neoadjuvant chemotherapy before debulking surgery. We performed a subanalysis with 32 neoadjuvant chemotherapy cases in our data; however, we could not find any significance between preoperative CA-125 and OS, PFS, and PFI on linear regression (p=0.23, p=0.30, p=0.25). In addition, in another study focused on the preoperative level of CA-125 in the indication of primary debulking surgery (21), the authors reported that it correlated with the feasibility of optimal surgery, OS, and PFS; thus, we also performed a subanalysis with the advanced-stage group in our data. On chi-square test for the relation with optimal surgery, there was no significance (p=0.36). Linear regression with OS and PFS also yielded no significance (p=0.63, p=0.30).
This study has a couple of limitations. First, this was a retrospective study of data from a single center. Second, our study only assessed a small sample size. Specifically, the early-stage group was small, and platinum resistance was noted in only four cases in this group. Further studies with larger datasets are needed.
This study demonstrated that the serum CA-125 level after chemotherapy is correlated with clinical outcomes in ovarian cancer. It can especially be used to predict platinum resistance.
Footnotes
Authors’ Contributions
DG HONG conceived of the presented idea and supervised the study. J LEE performed the analytic calculations. Both DG HONG and J LEE contributed to the draft of the manuscript. J LEE and JM KIM processed the clinical data. YH LEE designed the figures and revised the tables. GO CHONG helped supervise the study. All Authors discussed the results and contributed to the final manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to declare regarding this study.
- Received October 28, 2021.
- Revision received November 17, 2021.
- Accepted November 19, 2021.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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