Clinica Chimica Acta 440 (2015) 143–151

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Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim

Invited critical review

ROMA, an algorithm for ovarian cancer Anita Monika Chudecka-Głaz ⁎ Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland

a r t i c l e

i n f o

Article history: Received 1 August 2014 Received in revised form 3 November 2014 Accepted 14 November 2014 Available online 20 November 2014 Keywords: ROMA HE4 CA 125 Ovarian cancer

a b s t r a c t Improvement of survival in ovarian cancer may be achieved through early diagnosis and modification of treatment. Although abnormalities in the adnexal region are frequently observed in transvaginal ultrasound, interpretation may be equivocal in some cases. If neoplastic tumor is suspected, a wide range of tests and algorithms may be applied. Risk of Malignancy Algorithm (ROMA), as first described by Moore in 2009, is one of the most popular approaches. The clinical utility of this regression model has been demonstrated in both pre- (75.6% sensitivity and 74.8% specificity) and post-menopausal (92.3% sensitivity and 74.7% specificity) women. These findings have been independently confirmed in a number of publications. The sensitivity and specificity of ROMA may, however, be improved with inclusion of supplemental data, such as age and ultrasound findings. Because of its simplicity, ROMA is a reliable tool characterized by high accuracy and reproducibility to stratify patients into a high or a low ovarian cancer risk. © 2014 Elsevier B.V. All rights reserved.

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . 1.1. Ovarian cancer . . . . . . . . . . . . . . . 1.2. Various diagnostic algorithms for ovarian cancer 2. ROMA . . . . . . . . . . . . . . . . . . . . . . 2.1. CA125 . . . . . . . . . . . . . . . . . . . 2.2. HE4 . . . . . . . . . . . . . . . . . . . . 2.3. Principles of ROMA . . . . . . . . . . . . . 2.4. ROMA in clinical trials . . . . . . . . . . . . 2.5. Conclusions . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction 1.1. Ovarian cancer Ovarian cancer is responsible for the largest number of deaths due to gynecologic tumors in Europe and North America. It ranks second after cervical cancer worldwide. Approximately 85–90% of malignant ovarian tumors are epithelial tumors. It is estimated that ovarian cancer affects 238,719 women worldwide and causes more than 150,000 deaths annually. This ranks ovarian cancer in seventh place in terms of incidence

⁎ Corresponding author at: Al. Powstańców Wielkopolskich 72, PL-70-111 Szczecin, Poland. Tel.: +48 91 4661332; fax: +48 91 4661334. E-mail address: [email protected].

http://dx.doi.org/10.1016/j.cca.2014.11.015 0009-8981/© 2014 Elsevier B.V. All rights reserved.

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143 143 144 145 145 146 146 148 149 149

among malignant tumors in women and eighth with respect to death due to malignant tumors in women worldwide. Globally, it accounts for about 4% of all new malignant tumors among women. In developed countries, ovarian cancer ranks fifth in incidence (99,752 cases per year) and sixth in mortality (65,892 deaths per year) for malignant tumors among women (Fig. 1) [1]. Clinical symptoms are not well manifested in early stages of the disease, resulting in late diagnosis and poor prognosis. Five-year survival in ovarian cancer ranges from 30 to 50%, with considerable variation depending on a clinical stage: up to 70% for FIGO stage I (tumor confined to the ovaries) and FIGO II (tumor involves one or both ovaries with pelvic involvement — below the pelvic brim), and only about 20–40% for FIGO stage III (tumor involves one or both ovaries with cytological or histological confirmed spread to the peritoneum outside the pelvis and/or metastases to the retroperitoneal lymph nodes) and FIGO stage IV (distant metastases other than

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peritoneal metastases) [2]. Possible improvement of survival may be related to better diagnostics at an early stage of the disease and advances in treatment in view of its pathogenesis and its biologic heterogeneity [3].

1.2. Various diagnostic algorithms for ovarian cancer Abnormalities of adnexal region are frequently observed in transvaginal ultrasound. To a large extent these lesions are benign. As

Fig. 1. Cancer incidence and mortality in women populations.

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145

Fig. 1 (continued).

such, ultrasound imaging combined with gynecologic exam and proper anamnesis is generally sufficient to establish diagnosis. Unfortunately, ultrasound imaging is equivocal in some cases. Several years ago the only way to enhance diagnosis was to measure CA-125 in suspected ovarian cancer. Because of its low specificity, other approaches were considered including the development of algorithms that combined different markers, laboratory tests and diagnostic imaging [4–9]. Suspicious ultrasound imaging studies can now be supplemented with a wide range of tests and algorithms, including the most frequent, i.e., ROMA, Risk of Malignancy Index (RMI), OVA1 and LR2 index [5,10–25]. RMI, a widely used algorithm, involves specific ultrasound parameters, measurement of CA-125 and hormonal status to assign patients to a low or a high ovarian cancer risk [4,26,27]. Using a 200 cutoff value, the sensitivity and specificity of this algorithm are 64–94% and 82–92%, respectively, while the area under the receiver operating characteristics (ROC) curve (AUC) range is 0.931–0.945 [15,17,19]. The OVA1 algorithm is based on several serum biomarkers (CA-125, β2-microglobulin, transferrin, apolipoprotein A1 and transthyretin) combined with menopausal status. This algorithm was developed on the basis of proteomic studies with the exception of CA-125. It was approved by the FDA to differentiate benign and malignant adnexal lesions [28]. CA-125 should be determined using the Elecsys 2010 immunochemistry instrument (Roche Diagnostics). Transthyretin, transferrin, β2-microglubulin and apolipoprotein A1 should be measured by the SiemensBN™ II system. In post- and pre-menopausal patients, the sensitivity and specificity of this algorithm are 96% and 28% and 85% and 40%, respectively. The cutoff value is 5.0 for pre- and 4.4 for post-menopausal females [28]. Miller et al. [29] and Ueland et al. [30] demonstrated that specificity of the OVA1 test for epithelial

malignancy was 99%. Specificity in non-epithelial malignant ovarian, borderline epithelial and metastatic ovarian tumors was 82%, 75% and 76%, respectively. Moreover, the OVA1 test detected 76% of ovarian cancers in which CA-125 was normal. Despite improved sensitivity in differentiating ovarian tumors from 78% to as high as 99%, the OVA1 test caused a fairly large decrease in specificity, i.e., from 75% to 26% [22,29,30]. The LR2 model, a risk prediction model based on ultrasound imaging for the diagnosis of ovarian cancer in patients with suspicious ovarian lesions, was developed by the International Ovarian Tumor Analysis (IOTA) [9,11,12]. The parameters used in the LR2 model include age, presence of ascites, presence of abnormal flow in papillary lesions, maximum dimension of the solid structure, presence of irregular cystic lesions and presence of an acoustic shadow. Using a cutoff value of 10% [9] sensitivity was 93.8%, specificity was 81.9% and the AUC was 0.952. What is particularly interesting is that diagnostic test performance was better for pre- vs post-menopausal women. ROMA (Risk of Malignancy Algorithm) will be described in detail below. 2. ROMA 2.1. CA125 Studies on cancer antigen 125 (CA-125) started in the early 1980s and introduction of this antigen in ovarian cancer diagnostics was an important advance in gynecological oncology. The relationship between CA-125 and ovarian cancer was described in 1981 by Bast et al. [31]. Authors found that murine monoclonal antibody OC125 preferentially bound ovarian carcinoma vs cells from healthy ovarian tissue and non-neoplastic ovarian disease [31]. The CA-125 antigen is a heterogeneous mixture of glycoproteins with a molecular weight ranging

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between 200 and 1000 kDa. Depending on the diagnostic test used, cutoff values may be slightly different, but in 99% of healthy women CA125 is less than 35 U/mL [32]. CA-125 has high sensitivity, i.e., of up to 90%, but poor specificity, which often does not exceed 40%. Increased CA-125 in ovarian cancer depends on histologic findings and clinical tumor stage [33]. Increased CA-125 has been observed in many tumors including breast, endometrial, pancreatic and gastrointestinal tumors. Unfortunately, many benign gynecologic disorders including endometriosis, genital inflammation, pregnancy and menstruation are also associated with increased CA125 [34–36]. As such, CA-125 is not a good independent marker for diagnosis or screening of early ovarian cancer [37–39]. However, CA-125 is very useful to monitor ovarian cancer treatment [37]. In fact, the Gynecological Cancer Intergroup has recommended that CA-125 be used alone to assess treatment effectiveness during chemotherapy [40]. Yedema et al. [41] and Sorensen et al. [42] confirmed the significance CA-125 in the differential diagnosis of primary ovarian cancer and metastatic tumors in the ovary derived from gastrointestinal tract. A CA-125 to CEA ratio above 25 indicates a high probability of ovarian cancer with 91% sensitivity and 100% specificity [41]. The role of CA-125 as a prognostic factor remains controversial due to conflicting scientific studies [43,44]. In view of its good sensitivity in diagnosing ovarian cancer, CA-125 continues to be the subject of much research. Numerous reports indicate that combining CA-125 with other diagnostics, i.e., laboratory and imaging, significantly improves specificity [4,6,7,27,45,46]. 2.2. HE4 Recently, human epididymis protein 4 (HE4) has become one of the most intensively studied tumor markers for ovarian cancer [47–51]. This protein was first identified in epididymal epithelial cells and initially described as an inhibitor of proteases involved in spermatogenesis. HE4 protein has a WAP-type four-disulfide core (WFDC) domain encoded by the WFDC2 gene [52,53]. WAP domain proteins, including HE4, are low molecular weight proteins involved in many cellular processes including growth and differentiation. Although its function remains unclear, HE4 appears involved in neoplastic processes including adhesion, migration and growth of tumor cells [54,55]. Bingle et al. [56,57] and Galgano et al. [58] reported that HE4 was expressed in many normal epithelial tissues including the epididymal epithelium, the epithelium of female genital organs (endocervical, endometrial, fallopian tube, Bartholin's gland), the epithelium of the oral cavity, nose and upper respiratory tract, the epithelium of mammary ducts, kidney excretory ducts, large and small salivary glands, as well as anterior pituitary cells and thyrocytes. HE4 was poorly expressed in different parts of the gastrointestinal tract. Studies demonstrated increased HE4 protein in ovarian cancer cells [47,59–61] differentiated expression in breast cancer cells [62] and in numerous cell lines: OVCAR-3 and OVCAR-4 (ovary), HT-29, COL0205, HCT-116 (intestine), MALME-3M (melanoma), A498 and MCF-7 (breast) and 786-0 (kidney) [63]. However, it should be noted that despite weak or high expression in epithelial tumors of the lung, breast or pancreas, the highest expression has always been observed in the tissues from patients with ovarian cancer [58]. Drapkin et al. [49] demonstrated increased expression of HE4 in ovarian cancer cells. Expression was associated with histopathology, i.e., endometrioid carcinomas (100%), serous carcinomas (93%), clear cell carcinoma (50%) and mucinous carcinoma (0%). HE4 was not expressed in the epithelium covering the ovary. It was, however, expressed in the metaplastic epithelium of Müllerian inclusion cysts. The latter finding may be of importance relevant to ovarian cancer etiopathogenesis. Degree of tumor differentiation appears related to HE4 expression, i.e., high grade serous cancer (HGSC) (100%) and low grade serous cancer (LGSC) (79%) [55]. Subsequent studies confirmed that HE4 was released into the circulation and had better specificity

than CA-125 in diagnosing ovarian cancer because it was less frequently increased in benign disease [64–74]. HE4 is unaffected by the menstrual cycle, i.e., similar concentrations have been observed during menstrual, proliferative and secretory phases. Hormonal contraception also has no effect on serum HE4 [73,74]. Lack of increased HE4 in endometrial cysts is important for differentiating young pre-menopausal women in which CA-125 can reach concentrations comparable to those observed in malignant ovarian tumors [75–77]. Preoperative serum HE4, alone and in combination with CA-125, may predict response to platinum-based therapy as well as disease-free and overall survival [78–84]. Increased HE4 before surgery in patients with ovarian cancer can predict benefit of cytoreductive surgery [85,86]. At the same time, HE4 concentration during neoadjuvant chemotherapy correlates very well with response [24,25]. HE4 can also identify ovarian cancer recurrence at early stages [87–89]. 2.3. Principles of ROMA Lack of correlation between CA-125 and HE4 in randomly selected groups of patients and strong correlation in moderately and poorly differentiated ovarian cancers suggest that both markers may be complementary in patients with possibly neoplastic lesions in the adnexa. Numerous studies have demonstrated a significant improvement of sensitivity and specificity in predicting ovarian malignancy when these two markers are used together [6,7,10,12,46,70,90–95]. In 2008, Moore et al. [96] observed that among various well-known biomarkers, HE4 had the highest sensitivity especially in stage I disease. Moreover, the sensitivity of CA-125 increased from 43% to 76.4% when measured and interpreted with HE4. In 2009, Moore et al. [6] first described the predictive risk assessment model for the diagnosis of malignant epithelial ovarian tumors in women with pathological pelvic masses. This multicenter prospective study was composed of 248 pre- and 283 post-menopausal women. The logistic regression model had 76.5% sensitivity and 74.8% specificity and 92.3% sensitivity and 74.7% specificity for pre- and post-menopausal women, respectively. The authors used a commercial HE4 enzyme immunoassay (EIA) (Fujirebio Diagnostics, Malvern, PA) to determine HE4 and the Architect CA125II assay (Abbott Diagnostics, Abbott Park, IL) to measure CA-125 in the serum. A subsequent study performed in 2011 by the same research group became the basis for approval by the United States Food and Drug Administration (FDA) [7]. ROMA is a quantitative test based on the serum concentration of CA125 and HE4 combined with menopausal status (Fig. 2). Cut-off values depend on laboratory methods, hormonal status and differ for preand post-menopausal women. The test, approved by the FDA in June 2012, is intended for patients that meet the following criteria: ✓ Age over 18 years. ✓ Presence of a lesion in the appendages eligible for surgery, not yet transferred to the reference center. ✓ The final interpretation of ROMA results must be combined with clinical assessment and results of independent radiological examinations. ✓ The algorithm cannot be used as a screening test, as an independent diagnostic test, in pregnant women, in women treated for neoplasm and during chemotherapy. ✓ Presence of rheumatoid factor in a concentration greater than 250 IU/mL in blood serum can affect the calculated ROMA value. ROMA as approved by the FDA was based on the HE4 EIA by Fujirebio Diagnostics and chemiluminescent microparticle Architect i200S immunoassay (http://www.eccessdata.fda.goov/cdrh_docs/ reviews/K193358.pdf) [97]. At present, there are four generally accepted laboratory methods to calculate ROMA score and stratify patients into high or low risk groups. The selected tests and cut-off points are

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147

WOMEN WITH PELVIC MASS

BLOOD TEST FOR CA 125 AND HE4

PREMENOPAUSAL

*

POSTMENOPAUSAL

*

*

PI=-12+2.38 LN[HE4]+0.0626 LN[CA125]

*

PI=-8.09+1.04 LN[HE4]+0.732 LN[CA125]

ROMA ALGORITHM CALCULATION: ROMA VALUE [%] = EXP (PI) /[1+EXP(PI)*100

ASSIGNMENT OF PATIENT TO HIGH-RISK OR LOW-RISK OF OVARIAN CANCER

Fig. 2. Principles of algorithm ROMA.

presented (Table 1). The four test kits used to calculate the ROMA algorithm are described: A. HE4 EIA assay [Kit No. 404-10], Fujirebio Diagnostics AB, Goteborg, Sweden and ARCHITECT CA125 II assay [Reagent Kit No. 2K45], Abbott Diagnostics, Illinois, USA. The HE4 EIA is an enzyme immunometric assay for quantitative determination of HE4 in human serum. It is a solid-phase noncompetitive immunoassay based upon the direct sandwich technique using two mouse monoclonal antibodies, 2H5 and 3D8, directed against epitopes in the C-WFDC domain of HE4. The ARCHITECT CA125 II assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of OC CA125 defined antigen in human plasma and serum on the ARCHITECT i2000SR System. The ARCHITECT CA125 II assay is a two-step immunoassay that determines the presence of OC 125 defined antigen using CMIA technology, referred to as Chemiflex. Manufacturer claims are 100% sensitivity, 74.5% specificity, 13.8% PPV and 100% NPV for pre- and 92.3% sensitivity, 76.8% specificity, 50% PPV and 97.5% NPV for post-menopausal women [98]. B. Elecsys HE4 assay [Kit No. 05950929190] and Elecsys CA125 II assay [Kit No. 11776223322], Roche Diagnostics Ltd, Rotkreuz, Switzerland.

Elecsys® HE4 and CA125 II are electro-chemiluminescence immunoassays (ECLIA) for the quantitative determination of human epididymal protein 4 (HE4) and CA125 in serum and plasma. Both are one-step sandwich assays traceable, i.e., HE4 EIA Fujirebio Diagnostic, Inc. for HE4 and Enzymun-Test CA125 II for the CA-125 II RIA by Fujirebio Diagnostic, Inc. for CA125. Manufacturer claims are 83.3% sensitivity, 75.6% specificity, 64.9% PPV and 90% NPV for all patients studied with stage I-IV ovarian cancer regardless of menopausal status [99]. C. ARCHITECT HE4 assay [Reagent Kit No. 2P54] and ARCHITECT CA 125 II assay [Reagent Kit No. 2K45], Abbott Diagnostics, Illinois, USA. The ARCHITECT HE4 and CA125 II are two–step immunoassays for the quantitative determination of HE4 antigen and OC 125 defined antigen in serum using Chemiluminescent Microparticle Immunoassay (CMIA) technology. The ARCHITECT HE4 kit has the same intended use, type of specimen, antigen detected, capture and detection antibody as Fujirebio HE4 EIA. Basic differences concern the instrument system (manual for Fujirebio Diagnostics kit, automatic ARCHITECT cSystem for Abbot Diagnostics kit) and operation principles (Chemiluminescent Microparticle Immunoassay — CMIA for Abbot Diagnostics kit and Manual Enzymatic Immunoassay — EIA for Fujirebio Diagnostics kit). Manufacturer claims are: 87.3%

Table 1 Interpretation of ROMA results depending on the used and commercially available diagnostic tests. HE4 EIA + ARCHITECT II CA125

HE4 ARCHITECT + CanAg CA125

Premenopausal High-risk ≥11.4 Low-risk 11.4

Elecsys HE4 + Elecsys CA125

ARCHITECT HE4 + ARCHITECT II CA 125

≥13.1 13.1

≥12.5 12.5

≥7.4 7.4

Postmenopausal High-risk ≥29.9 Low-risk 29.9

≥27.7 27.7

≥14.4 14.4

≥25.3 25.3

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sensitivity, 75.3% specificity, 60.6% PPV and 93.2% NPV for all women; 79.4% sensitivity, 75.4% specificity, 36% PPV and 95.5% NPV for pre-; and 89.7% sensitivity, 75.2% specificity, 73.8% PPV and 90.3% NPV for post-menopausal women [100]. D. HE4 EIA assay [Kit No. 404-10] and CanAg CA125 EIA assay [Kit No. 400-10], Fujirebio Diagnostics AB, Goteborg, Sweden. Principles of the HE4 EIA method are described above. The CanAg CA125 EIA is a solid-phase, non-competitive EIA based on the direct sandwich technique intended for the quantitative determination of cancer-associated antigen CA-125 in serum. Manufacturer claims are 93% sensitivity, 75% specificity, 57% PPV and 97% NPV for stratification of stage I–IV patients into the high-risk group [101].

2.4. ROMA in clinical trials Although a number of publications have confirmed the usefulness of the regression model ROMA [45,50,69,91,95,102–107], others have not with other algorithms [9,11,12,19,108–112] or single markers [13,65, 113–115] (Table 2). Ruggieri et al. [106] found that HE4 was much more specific and more accurate than CA-125 in differentiating benign and malignant ovarian lesions. Combination of both markers in ROMA also demonstrated a very good accuracy in those with high ovarian cancer risk. In this study, sensitivity was 95.8% for all women, 81% for preand 96% for post-menopausal women. Ortiz-Munoz et al. [103] demonstrated that ROMA may contribute to proper stratification of patients in clinically unclear cases. By far, this study demonstrated best test performance with 93.1% sensitivity, 90.7% specificity, 71.1% NPV and 98.2% PPV. Studies conducted by Kim et al. [91] and a meta-analysis by Li et al. [95] also demonstrated that CA-125 and HE4 in the ROMA regression model significantly increased the accuracy of stratifying patients into high or low risk groups. The usefulness of the ROMA model in early ovarian cancer was shown by Lenhard et al. [104]. Some authors [69,105,116] indicated increased benefit with ROMA vs traditionally

measured CA-125 and HE4. Using this approach, a specificity of 99% was achieved in post-menopausal patient, vs an expected specificity of 75% [105]. Similarly, Sandri et al. [116] showed a statistically better AUC value for ROMA vs CA-125 in post-menopausal patients. Chan et al. [102] and Kadija et al. [50] demonstrated that ROMA might be an important diagnostic test in pre-menopausal patients to improve performance with respect to extent of malignancy. This finding is particularly relevant in the differentiation of endometrial cysts which frequently occur in this group of patients [45]. In pre-menopausal women, ROMA classified 96% of histopathologically confirmed benign ovarian changes as low-risk lesions [50]. Montagnana et al. [65] demonstrated that ROMA successfully differentiated benign from malignant tumors in post-menopausal patients but showed no statistical difference when compared to HE4 alone. Molina et al. [115] showed a 3.2% increase in specificity when CA-125 was added to HE4 with ROMA. Pitta et al. [114] demonstrated that HE4 or ROMA in patients with ultrasound evident lesions in uterine appendages was not diagnostically superior to symptom index (SI) or CA-125 alone. Symptoms observed in the course of ovarian cancer were divided into relevant groups: gastrointestinal tract symptoms; symptoms associated with food intake; and symptoms associated with pain. Presence of one symptom from each group lasting for about a year, occurring for 12 days a month and worsening of those symptoms indicated a probability of diagnosing a malignant ovarian tumor. Results demonstrated that ROMA was more useful than HE4 but not CA-125 in differentiation of adnexal lesions in early stage disease. However, it should be noted that the authors did not use generally accepted diagnostic tests to calculate ROMA. For example, CA-125 was determined by OM-MA assay (Siemens Medical Solutions Diagnostics, Tarrytown, USA). Sensitivity and NPV differed significantly from the values obtained using traditional methods of analysis. Van Gorp et al. [108] Jacob et al. [113] and Kajiser et al. [11] did demonstrated better test performance using independent measurement of CA-125 or HE4 in selected groups of patients. Studies presented at Wiesbaden 2012 demonstrated that the performance of ROMA could be improved by including age of the patient

Table 2 Sensitivity, specificity, PPV, and NPV of ROMA for stratification of patients with pelvic masses reported in the literature. Author

Moore RG et al. [6] Molina R et al. [114] Moore RG et al. [7] Anton C et al. [17] Anton C et al. [17] Partheen K et al. [114] Van Gorp T et al. [19] Novotny Z et al. [119] Karlsen et al. [116] Ortiz-Munoz et al.[103] Lenhardt et al. [104] Kalapotharacos et al.[105] Sandri et al. [116] Montagnana et al.[65]

ROMA cut-off point [%]

M — 27.7 PM — 13.1 M — 27.7 PM — 13.1 M — 27.7 PM — 13.1 M — 39.7 PM — 13.9 M — 27.7 PM — 13.1 M — 26 PM — 17 M — 12.5 PM — 14.4 M — 37.7 M — 25.3 PM — 7.4 M — 29.9 PM — 11.4 M — 25.3 PM — 7.4 M — 10.4 PM — 4.6 M — 25.3 PM — 7.4 M — 14.4 PM — 12.5

Study population N

Diagnostic methods

M — 283 PM — 248 All — 495

CA 125-CMIA HE4-EIA CA125-CMIA HE4-CMIA CA 125 — CMIA HE4 — EIA CA 125-ECLIA HE4-EIA CA 125-ECLIA HE4-EIA CA 125-CMIA HE4-EIA CA125-EIA HE4-EIA CA125-CMIA HE4-CMIA CA125-CMIA HE4-CMIA CA125-ECLIA HE4-ECLIA CA 125-CMIA HE4-CMIA CA 125-ECLIA HE4-EIA CA 125-CMIA HE4-CMIA CA 125-EIA HE4-EIA

M — 217 PM — 255 M — 73 PM — 47 M — 73 PM — 47 M — 276 PM — 98 All — 374 M — 256 M — 597 PM — 621 M — 118 PM — 61 M — 256 PM — 271 M — 154 PM — 123 M — 191 PM — 158 M — 53 PM — 51

Sensitivity [%]

Specificity [%]

PPV [%]

All

PM

M

All

PM

M

All

PM

M

All

NPV [%] PM

M

88.7

76.5

92.3

74.7

74.8

74.7

60.1

33.8

74.0

93.9

95

92.6

90.1

74.1

95.2

87.7

88.9

83.1

74

44.4

88.9

95.8

96.6

92.5

88.1

81.3

90.2

74.9

74.2

76

38.1

17.8

56.1

97.3

98.3

95.8

75.9

77.8

63.9

81.8

79.3

97.3

–

–

–

–

–

–

74.1

77.8

72.2

75.8

69

81.1

–

–

–

–

–

–

–

75

75

–

81

87.1

–

60.7

62.8

–

90.7

90.7

84.7

66.7

91.0

76.8

87.8

58.8

71

60.5

74.3

88.2

90.4

83.3

–

–

85.7

–

–

95

–

–

62.06

–

–

98.65

94.8

91.8

92.6

76.5

40.2

73.5

–

–

–

–

–

–

93.1

90

94.7

90.7

82.4

94.1

71.1

60

78.3

98.2

96.6

98.8

76.6

66.6

72.1

–

–

–

–

–

–

–

–

–

–

82

99

–

–

–

–

–

–

–

–

–

91.2

85.2

91.5

–

–

–

–

–

–

–

–

–

–

53.5

82.5

–

80.6

84.6

All — PM + M; PM — premenopausal; M — postmenopausal; ECLIA-electro-chemiluminescence immunoassay; EIA — enzyme immunometric assay; CMIA — chemiluminescent microparticle immunoassay.

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(ROMA CPH). Using this approach, similar diagnostic values were obtained for RMI (0.959) and ROMA (0.958). A higher AUC value for ROMA (0.962) was obtained by authors by including age and ultrasound parameters as measured in the RMI index (ROMA CPH + UL) [5,24,25]. Accuracy may also be improved by correcting for non-specific increases in HE4 due to smoking, renal failure, acute myocardial infarction, or slightly increased serum creatinine [24,64]. Additional prospective multicenter studies using ROMA are needed to reduce bias. Previously conducted studies on ROMA were limited to epithelial ovarian malignancies that excluded malignant germ cell tumors, gonadal tumors, epithelial tumors of borderline malignancy and metastatic lesions in the ovary [12]. Since 1990, numerous centers around the world have successfully used the RMI index. Following the introduction of ROMA, several studies have compared these two approaches [15,17,19,66,108,117]. Both methods appear comparable with respect to assessment of pathological changes in the pelvis [17, 19,108,117]. Sensitivity and specificity of ROMA vs RMI were: 84.7% and 76.8 v. 76% and 92.4% [19]; 94.8% and 81.5% vs 96% and 81.5% [117]; and 75.9% and 81.8% vs 77.8% and 87.9% [17]. Moore et al. [66] reported much greater sensitivity of ROMA (85.3%) vs the RMI index (64.7%) in detecting ovarian cancer especially at early disease stage. Recently, the logistic regression model LR2 proposed by IOTA [9,118] has become increasingly more popular. This simple approach does not require additional markers and has 95–98% sensitivity, 73–86% specificity and 0.92–0.95 AUC [9]. Because similar parameters are included in the most popular algorithms (ROMA, RMI, OVA1, LR2), it is reasonable that facilities with lower referral level would opt for the most convenient and reproducible approach. Additional factors for consideration would include sophistication of laboratory facilities, diagnostic imaging capability, etc. ROMA has also been studied for its prognostic ability in ovarian cancer [45,79]. A high ROMA value in the pre-operative period was associated with more advanced FIGO stage, suboptimal cytoreduction, presence of ascites, positive cytology of peritoneal fluid, lymph node involvement [45] shorter disease-free, progression-free and overall survival as well as resistance to platinum-based drugs [79]. Unfortunately, recurrence takes place in 70% of patients with ovarian cancer, mostly within the first three years following treatment despite surgical success and optimal chemotherapy. Monitoring CA-125 during the first course of chemotherapy is recommended [120]. The latest studies, however, have shown that HE4 measurement may also be beneficial [82]. However, the value and methods of patient follow-up after primary treatment is currently the subject of many studies and scientific discussions. Until recently, monitoring of patients with ovarian cancer consisted of gynecologic examination and CA-125 measurement at equal time intervals, i.e., every three months in the first two years and then every six months for up to five years after the end of treatment or until progression. The rationale for regular CA-125 measurement for detecting early recurrence before onset of clinical symptoms was questioned following randomized phase three studies published by Rustin et al. (OV05-EORTC 55955) in 2009 [121]. It was shown that early implementation of treatment for recurrence based solely on increased CA-125 did not influence overall survival and, in fact, significantly deteriorated quality of life. In June 2008, the FDA accepted HE4 as an adjuvant marker for monitoring ovarian cancer treatment and detecting early recurrence. Similar studies were also presented by Granato et al. [122] and Anastasi et al. [123]. If currently conducted studies confirm that early treatment for ovarian cancer recurrence does not influence overall survival, then the usefulness of CA-125 and HE4 in will be significantly diminished. To date, there have been no studies on ROMA in monitoring treatment. 2.5. Conclusions ROMA is characterized by high accuracy and repeatability in stratifying patients into high or low ovarian cancer risk. This is particularly

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evident in post-menopausal patients with almost perfect accuracy in young women with endometrial ovarian lesions. The use of ROMA in these patients is advantageous because it avoids unnecessary or excessively radical surgery. An additional benefit is that ROMA is reproducible approach in the hands of young inexperienced doctors, physicians with little experience in the field of diagnostic ultrasonography or doctors working in hospitals with a lower referral base. Despite its current usefulness, it is likely that ROMA sensitivity and specificity can be further improved by inclusion of additional factors such as age, ultrasound findings and exclusion of non-specific increases in HE4. Large currently underway studies should bring provide clearer and more conclusive answers in the near future. References [1] Ferlay J, Soerjomataram I, Ervik M, et al. Globocan 2012 v 1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No . 11. 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