What is the clinical role of CA‑125 in diagnosing, risk‑stratifying, monitoring treatment, and following up ovarian epithelial cancer, and why is it not recommended for screening average‑risk women?

CA-125 in Ovarian Epithelial Cancer: Clinical Roles and Screening Limitations

Diagnosis

CA-125 aids diagnosis of ovarian cancer but should never be used in isolation—it must be interpreted alongside imaging and clinical findings. 1

• CA-125 is elevated in approximately 85% of patients with advanced epithelial ovarian cancer, making it useful for diagnostic workup when malignancy is suspected 1
• Only 50% of stage I (early) ovarian cancers have elevated CA-125, severely limiting its utility for early disease detection 1, 2
• The marker is most reliable in high-grade serous carcinoma (70% of epithelial ovarian cancers) but has poor sensitivity in other histologic subtypes including mucinous, clear cell, endometrioid, and low-grade serous carcinomas 2

Diagnostic Algorithm:

• Measure serum CA-125 as part of initial workup when ovarian cancer is suspected 1
• For mucinous tumors specifically, also measure CEA and CA 19-9—a CA-125/CEA ratio >25:1 favors ovarian origin over gastrointestinal metastasis 1, 2
• If CEA or CA 19-9 is elevated in suspected mucinous tumors, perform endoscopy to exclude gastrointestinal primary 1
• Ultrasound-based models (IOTA Simple Rules or IOTA ADNEX) are superior to CA-125 alone for distinguishing benign from malignant ovarian masses 1

Critical Pitfall:

CA-125 lacks specificity and is elevated in numerous benign conditions including endometriosis, pelvic inflammatory disease, ovarian cysts, pregnancy, menstruation, cirrhosis, heart failure, renal failure, and pleural effusions 1, 2, 3. Values can reach >1000 U/mL in benign conditions, further limiting diagnostic utility 3.

Risk Stratification

Preoperative CA-125 levels help predict surgical resectability and guide referral to gynecologic oncologists. 4

• Higher preoperative CA-125 values correlate with advanced disease stage and may identify patients where optimal cytoreduction is less achievable 4
• Perioperative changes in CA-125 after primary surgery and the nadir value after primary chemotherapy are associated with patient outcome 4
• CA-125 should be measured before each chemotherapy cycle to monitor treatment response 1

Treatment Monitoring

CA-125 is highly reliable for monitoring response to cytotoxic chemotherapy in established epithelial ovarian cancer, particularly high-grade serous carcinoma. 2, 5

• There is very high correlation between CA-125 levels and clinical course during chemotherapy 1
• CA-125 should be measured at every visit if initially elevated during active treatment 1
• CA-125 criteria for response and progression (GCIG criteria) must be combined with radiological and clinical assessment—never use CA-125 alone for treatment decisions 2
• The role of CA-125 in assessing response to targeted therapies (bevacizumab, PARP inhibitors) is not proven—use radiological and clinical assessment instead 2

Monitoring Protocol During Treatment:

• Measure CA-125 before each chemotherapy cycle 1
• Obtain CBC and chemistry profile as clinically indicated 1
• Perform pelvic examination every 2-3 cycles 2

Follow-Up and Recurrence Detection

CA-125 monitoring during follow-up detects recurrence months before clinical symptoms, but early treatment based solely on rising CA-125 does not improve survival. 5

Follow-Up Schedule:

• Visits every 2-4 months for 2 years, then every 3-6 months for 3 years, then annually after 5 years 1
• Measure CA-125 at every visit if initially elevated 1
• Physical examination including pelvic exam at each visit 1
• CBC and chemistry profile as clinically indicated 1

Recurrence Detection:

• Rising CA-125 in asymptomatic patients typically precedes clinical relapse by 2-6 months 2
• Serial CA-125 measurements require two elevated values at least one week apart to confirm progression 2
• When CA-125 rises, obtain imaging studies (chest/abdominal/pelvic CT, MRI, or PET-CT) as clinically indicated 1

Critical Management Decision:

For patients with serially rising CA-125 after previous chemotherapy, immediate treatment is Category 2B recommendation, but clinical trials have shown that delaying treatment until symptomatic recurrence does not negatively impact overall survival 1, 5. This highlights the need for shared decision-making, as CA-125 elevations cause considerable anxiety and deterioration in quality of life without survival benefit from early intervention 5.

Why CA-125 Is NOT Recommended for Screening Average-Risk Women

Routine CA-125 screening is explicitly NOT recommended for the general population—randomized data do not support this approach. 2

Evidence Against Screening:

• Only 50% sensitivity for stage I ovarian cancer means it misses half of early malignancies 1, 2
• The positive predictive value of screening is only about 2% in average-risk women, meaning 98% of positive tests are false positives 2
• High frequency of false-positive results in benign conditions leads to unnecessary interventions 3, 6
• No mortality benefit has been demonstrated from CA-125 screening in average-risk populations 2

Special Populations:

• For women with BRCA mutations or strong family history, some clinicians monitor with CA-125 and transvaginal ultrasound, though prospective validation remains elusive 2
• The ROCA algorithm (using age and longitudinal CA-125 changes) may have utility in high-risk women but is not validated for average-risk screening 2
• The OVA1 test should NOT be used as a screening tool per FDA and Society of Gynecologic Oncologists guidance 2

Fundamental Problem:

CA-125 lacks both the sensitivity to detect early curable disease and the specificity to avoid excessive false positives, making it unsuitable as a screening test despite its value in monitoring established disease 1, 2, 3, 6.