Academic articles, April

Ovarian Cancer Screening: Current Evidence and Clinical Considerations

Asst.Prof. Woraphot Chaowawanit, MD
Gynecologic Oncology Unit, Department of Obstetrics and Gynecology,
Faculty of Medicine Vajira Hospital, Navamindradhiraj University

          Ovarian cancer is one of the most lethal gynecologic malignancies, often diagnosed at an advanced stage due to its non-specific symptoms. It is the sixth leading cause of cancer-related deaths among women worldwide, with an increasing incidence in Thailand, where approximately 7,000 women are diagnosed annually. Due to the aggressive nature of the disease and the challenges in early detection, effective screening strategies remain a subject of ongoing research.

The role of CA125 in screening
          CA125, a glycoprotein antigen, was first identified in the early 1980s by Bast et al. as a biomarker for ovarian cancer. It was initially discovered through research aiming to develop a serologic marker for epithelial ovarian carcinoma. The study demonstrated that CA125 was elevated in over 80% of patients with advanced ovarian cancer (1). Due to this association, CA125 was incorporated into clinical practice as a tool for diagnosing and monitoring ovarian cancer.
          Despite its early promise, subsequent research revealed significant limitations in using CA125 as a screening tool, primarily due to its lack of specificity and sensitivity. While it remains a valuable biomarker for tracking disease progression and treatment response in diagnosed patients, its role in screening remains controversial and is not recommended for routine population-based screening.

The Limitations of CA125 in Ovarian Cancer Screening
          The CA125 blood test is frequently utilized in ovarian cancer screening; however, it lacks sufficient specificity and sensitivity. Several factors contribute to its limitations:

1. Low Specificity: CA125 can be elevated in non-malignant conditions, including endometriosis, pelvic inflammatory disease, benign ovarian cysts, and other malignancies such as lung and colorectal cancer (2).

2. False Negatives in Early-Stage Cancer: Some early-stage ovarian cancers do not produce significant levels of CA125, leading to missed diagnoses (3).

3. Elevated Levels in Physiological States: Premenopausal women may have fluctuating CA125 levels due to the menstrual cycle or pregnancy, further limiting its reliability as a screening tool (4).

          Given these limitations, CA125 is not recommended as a standalone screening test for the general population but remains useful for monitoring treatment response and disease recurrence in diagnosed cases.

The Role of Ultrasound in Screening
          Transvaginal ultrasound (TVS) is another modality commonly used to evaluate ovarian morphology. In large-scale trials, such as the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), TVS was studied in combination with CA125 testing.

UKCTOCS: A Comprehensive Study on Ovarian Cancer Screening
          The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) was one of the largest studies evaluating the effectiveness of ovarian cancer screening. The trial, which included 202,638 postmenopausal women aged 50-74 years, was conducted over a period of 16 years and assessed whether multimodal screening (MMS) using CA125 levels with the Risk of Ovarian Cancer Algorithm (ROCA) alongside transvaginal ultrasound (TVS) could reduce ovarian cancer mortality.

Participants were randomly assigned into three groups:
– Multimodal screening (MMS) group: Women underwent CA125 testing combined with the Risk of Ovarian Cancer Algorithm (ROCA), with additional TVS for those with abnormal results.
– Ultrasound screening (USS) group: Women underwent TVS alone.
– Control group: Women received no routine ovarian cancer screening.

          The final results, published in The Lancet in 2021, revealed that while the screening strategies improved early-stage cancer detection rates (i.e., more stage I and II cancers were diagnosed in the screened groups), they did not result in a significant reduction in ovarian cancer mortality. This outcome was attributed to the aggressive nature of high-grade serous carcinoma (HGSC), which progresses rapidly between screening intervals. The study concluded that despite earlier detection, current screening methods are insufficient to impact overall survival rates and are not recommended for routine use in the general population (5).

Current Recommendations and Clinical Implications
         Ovarian cancer screening guidelines have been established by various professional organizations, reflecting a consensus on the current understanding of screening efficacy and associated risks.

U.S. Preventive Services Task Force (USPSTF)
          USPSTF advises against routine screening for ovarian cancer in asymptomatic women who do not have known high-risk hereditary cancer syndromes. This recommendation is based on evidence indicating that the potential harms of screening outweigh the benefits, primarily due to the low prevalence of ovarian cancer in the general population and the high rate of false-positive results leading to unnecessary interventions (6).

National Comprehensive Cancer Network (NCCN)
          NCCN does not endorse routine ovarian cancer screening for average-risk, asymptomatic women. However, for women at increased genetic risk—such as those with BRCA1 or BRCA2 mutations or Lynch syndrome—the NCCN recommends a thorough risk assessment, genetic counseling, and consideration of risk-reducing strategies, including salpingo-oophorectomy (7).

European Society for Medical Oncology (ESMO)
          ESMO’s guidelines align with those of other organizations, advising against routine screening in the general population due to insufficient evidence of mortality reduction. For high-risk individuals, ESMO emphasizes personalized risk assessment and discusses potential preventive measures, including prophylactic surgery (8).

American College of Obstetricians and Gynecologists (ACOG)
          ACOG concurs with the aforementioned guidelines, recommending against routine screening for ovarian cancer in average-risk women. They highlight the importance of individualized care and shared decision-making, particularly for those with a family history suggestive of hereditary cancer syndromes (9).

Clinical Implications
          The consensus across these organizations underscores the current limitations of ovarian cancer screening methods. For average-risk women, the potential harms of screening—such as false positives, unnecessary surgeries, and associated complications—outweigh the benefits. Therefore, routine screening is not recommended.
          For women at high risk, a more proactive approach is warranted. This includes genetic counseling, consideration of risk-reducing strategies like prophylactic surgery, and individualized surveillance plans. Healthcare providers should engage in detailed discussions with these patients to navigate the complexities of risk and benefit, ensuring that decisions align with the patient’s values and preferences.
         In summary, while routine ovarian cancer screening is not advocated for the general population, high-risk individuals require tailored strategies to manage and mitigate their elevated risk. Ongoing research and advancements in screening technologies may, in the future, refine these recommendations to improve early detection and outcomes in ovarian cancer.

 References

1. Bast RC, Feeney M, Lazarus H, et al. Reactivity of a monoclonal antibody with human ovarian carcinoma. J Clin Invest. 1981;68(5):1331-1337.

2. Jacobs I, Bast RC. The CA 125 tumour-associated antigen: a review of the literature. Hum Reprod. 1989;4(1):1-12.

3. Buys SS, Partridge E, Black A, et al. Effect of screening on ovarian cancer mortality: the PLCO Cancer Screening Randomized Controlled Trial. JAMA. 2011;305(22):2295-2303.

4. Clarke-Pearson DL. Screening for ovarian cancer. N Engl J Med. 2009;361(2):170-177.

5. Jacobs IJ, Menon U, Ryan A, et al. Ovarian cancer screening and mortality in the UKCTOCS trial: a randomized controlled trial. Lancet. 2021;397(10290):1444-1453.

6. U.S. Preventive Services Task Force. Screening for ovarian cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;319(6):588-594.

7. National Comprehensive Cancer Network. Ovarian cancer, version 1.2022. JNCCN. 2022;19(2):191-202.

8. European Society for Medical Oncology. Ovarian Cancer Guidelines. ESMO Clinical Practice Guidelines. 2022.

9. American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 716. Obstet Gynecol. 2017;130(3):e146-e149.