Literature was searched in the Medline Database, using the following criteria: human epididymis protein 4 (HE4), ovarian carcinoma, CA125; and screening or diagnosis or prognosis or monitoring; and ovarian carcinoma or HE4 or human epididymis protein 4, or CA125. Filters are publication dates from January 1, 2008, to December 31, 2013. All of the titles were generated by the search, and the abstracts were reviewed for relevance, after which the full articles were obtained for those selected. The articles were evaluated by level of evidence (LOE) and strength of recommendation (SOR) according to the classifications provided in Tables 1 and 2, respectively.10,11 Earlier guideline articles and their references were also searched.4,8 The results of the literature search were structured according to the types of marker utility as presented in Table 3.
At present, the conclusion from these major trials is that owing to limitations of CA125 sensitivity and specificity, its use among asymptomatic women outside the context of a clinical trial cannot be recommended for general population screening (Table 4).4 However, CA125, in combination with transvaginal ultrasound, may have a role in early detection of ovarian cancer in women with hereditary alterations in the BRCA1 and BRCA2 tumor suppressor genes, where the lifetime risk of developing ovarian cancer is approximately 40% for BRCA1 carriers and 18% for BRCA2 carriers.22 However, there is as yet no evidence that ovarian cancer screening results in a stage shift to earlier stage disease, or that it reduces morbidity or mortality from ovarian cancer. The best prevention in these women is bilateral salpingooophorectomy.23–25
Algorithms to calculate the Risk of Malignancy Index (RMI) have been developed by Jacobs et al27 and by Tingulstad et al28 as RMI 1 and RMI 2, respectively. Both RMI scoring systems are the product of ultrasound score × menopausal score × CA125 concentration in kU/L (Table 5). The difference between the RMI 1 and the RMI 2 scores is the number of ultrasound findings considered. Three studies have compared the 2 RMI systems using score values above 200 to indicate malignancy. The validity of the RMI 1 and the RMI 2 scores was similar.28–30 Another algorithm was developed and validated in co-operation with a number of European centers specialized in ultrasound of the pelvis (International Ovarian Tumor Analysis group). The algorithm challenged the suggestion that the CA125 concentration added to ultrasound in distinguishing nonmalignant from malignant ovarian masses.31 In the hands of these expert centers, the ultrasound criteria only performed better than the RMI 1.32 The same group has, however, reintroduced CA125 in the latest version of their algorithm, Assessment of Different NEoplasias in the adneXa.33 The National Institute for Health and Care Excellence has introduced guidelines for early detection of ovarian cancer in symptomatic women for use by general practitioners.34 The potential advantages and disadvantages of the guidelines have been discussed with focus on the use of CA125 among premenopausal women where its increasing use may lead to waste of health care resources.35 The recommendations from different scientific societies are provided in Table 4.
Preoperatively, the initial stage of disease is an important prognostic factor. However, it has been suggested that in patients who had a preoperative CA125 concentration greater than 65 kU/L, the 5-year survival rates in univariate and multivariate analyses were found to be significantly lower as compared to patients who had values less than 65 kU/L. For the studies including early-stage disease (IA, B, C), the initial CA125 values would be more closely related to histology (serous vs nonserous) rather than prognosis within the serous population.36,37 Studies by Prat et al and Xu et al38,39 based on multivariate analysis suggested that the nadir concentrations after primary treatment and follow-up may provide prognostic information in terms of overall survival (OS). However, this information needs confirmation because it is not unusual to observe transient elevations in CA125 after chemotherapy, likely reflecting tumor necrosis and release of circulating CA125. Finally, there has been no consistent effort to differentiate between patients who have primary optimal cytoreduction (which can reduce CA125 before chemotherapy) and patients selected for neoadjuvant chemotherapy with interval cytoreduction, who must rely only on chemotherapy. As such, knowledge of single-point CA125 measurements would not change ongoing primary therapy and provides only limited prognostic information. The inconsistent results from different studies may also be attributed to the unspecific use of CA125 for all epithelial ovarian cancer types.
The European Group on Tumor Markers (EGTM) has recognized the challenges associated with planning, conducting, and reporting clinical tumor marker surveillance programs and now offers advice on how to design and conduct these types of studies.57 The European Society of Gynecologic Oncologists has recently advised against universally abandoning CA125 in the routine follow-up of all patients with ovarian cancer. Accordingly, CA125 monitoring should be considered in patients who (i) after complete response on primary treatment have been or are being treated as part of a clinical trial, (ii) would be eligible for (future) clinical trials on second-line treatment, (iii) will not have routine (3 monthly) follow-up including regular imaging, and (iv) are eligible for secondary surgery at recurrence.44 The current position of the EGTM is that CA125 is recommended for monitoring of patients if surveillance is likely to have clinical consequences (Table 4).
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