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Epithelial Ovarian Cancer: Screening, Biomarkers and Staging

Evelyn Reynolds, MD, gynecological oncology

Ovarian cancer, the silent killer, steals nearly 14,000 lives a year in the United States – killing about 75% of the women it afflicts. 

Although it represents 3 percent of new cancer cases in women, it’s responsible for 5 percent of the deaths. And, while survival percentages are in the 90s for stage I disease, just 20 percent of patients are diagnosed at this stage. Nearly two-thirds are diagnosed in stage III or IV, when survival drops to 37 percent and 25 percent, respectively. It's no wonder we are desperately searching for the keys to early detection.

Early diagnosis elusive

Early diagnosis is difficult for several reasons:
  • Symptoms can be mild and easily mistaken for natural age-related changes.
  • Ovarian cancer symptoms overlap significantly with classic GI or bladder problems.
  • We have not found a definitive early stage diagnosis test or biomarker.

Late diagnosis often is blamed on the idea that most cases are asymptomatic until the later stages of the disease. One study has reported, however, that 89 percent of stage I and II patients and 97 percent of stage III and IV patients did recall having symptoms before diagnosis.

These symptoms were associated significantly with ovarian cancer when they were present for less than a year and occurred more than 12 days a month:

  • Pelvic or abdominal pain
  • Urinary urgency or frequency
  • Increased abdominal size or bloating
  • Difficulty eating and quickly feeling full

We recommend patients presenting with these symptoms be worked up for potential GI and GYN issues concurrently.

Study results don't validate screening methods 

There's hope that screening could lead to early detection and lower overall mortality. Studies of both transvaginal ultrasound and CA-125 have not yet shown a clear correlation, however. Two large ongoing trials recently reported interim results: the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial, or PlCO, and the UK Collaborative trial of Ovarian Cancer Screening, or UKCTOCS.

PLCO

The objective of this study was to estimate whether screening with TVU and CA-125 can reduce mortality from ovarian cancer. The study included about 39,000 women age 55-74 with no prior history of lung, colorectal or ovarian cancer. Half were randomized to receive annual CA-125 tests and TVU for four years, plus two additional rounds of screening with CA-125 only.

  • Through four rounds of screening, the ratio of surgeries to cancers was high.
  • Most cases were detected at a late stage.
  • Cases detected through TVU only tended to be early stage, but this group represented just 14 cases.
  • TVU results continued to account for most of the unnecessary surgeries.
  • The effect of screening on mortality is not yet known.

UKCTOCS

This study also looked at the effect of ovarian cancer screening on mortality. It included about 203,000 postmenopausal women age 50-74 with no previous bilateral oophorectomy and no family history or other increased risk for ovarian cancer. Women randomized to the intervention arm were allocated to either the multimodal screening group, which included an annual CA-125 with TVU as a second line, or into the ultrasound screening group, which included annual screening with TVU only. 

Its initial results:
  • Almost half of the cancers detected were in stage I or II.
  • Specificity was higher in the multimodal group (fewer repeat tests and almost nine times fewer surgeries).
  • More borderline tumors were detected in the ultrasound-only group.
  • The effect of screening on mortality cannot yet be determined.

Biochemicalmarkers have distinct roles

Although we've seen a lot of excitement in the public media recently about the use of biomarkers in detecting ovarian cancer, it's important to understand their limitations. CA-125 and HE4 have been approved for monitoring of epithelial ovarian cancer, but neither has been shown effective as a general screen, and neither can stand alone as a detection or evaluation tool. The newest test, OVA1, is promising, but not perfect.

CA-125

CA-125 is a glycoprotein expressed by tissue derived from coelomic epithelium (pleura, pericardium, peritoneum) and Müllerian tissue (tubal, endometrial, endocervical). CA-125 is not expressed by the surface epithelium of normal ovaries, but it's overexpressed by serous tumors primarily and by some mucinous papillary tumors. 

CA-125 is elevated in 80 percent of patients with epithelial ovarian cancer – but in only 50 percent with stage I disease at diagnosis. It has not been established as a cost-effective screen for asymptomatic patients. It is, however, the only biomarker recommended for detecting recurrence and monitoring therapy.

HE4

Some EOCs do not express CA-125 but do express HE4, or human epididymis protein 4, so the two tests may be useful in combination. HE4 can be overexpressed by epithelial ovarian cancer tumors and circulate in the serum of patients with EOC. It's also less likely to be elevated falsely in the setting of benign neoplasms as compared to serum CA-125. HE4 can help differentiate endometriomas from malignant ovarian tumors. It also has greater specificity in the premenopausal age group. 

OVA1

The latest assessment getting attention is OVA1, approved by the FDA in 2009. The test combines the results of five proteins, including CA-125 II, and provides a score. A high probability of malignancy is indicated by a score of 5 for premenopausal patients and 4.4 for postmenopausal women. Early studies show the test improves the clinician's presurgical assessment – identifying the majority of patients with a malignancy that was missed by pre-op assessment alone.

This test does not take the place of clinical decision making, however, and should never be used as a screening or stand-alone test, until a mass is detected. Even then, if you know the mass needs to be removed, the benefits of adding an OVA1 test to reinforce your conclusion often don't justify the cost. It costs $650 alone or $820 with FSH and LH. If your risk assessment is equivocal, getting a CA-125, followed by OVA1 may help decide on referral to a gynecologic oncologist, especially in areas where access to specialty care is limited.

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