Diagnostic measures comparison for ovarian malignancy risk in Epithelial ovarian cancer patients: a meta-analysis

Abstract

Epithelial ovarian cancer has become the most frequent cause of deaths among gynecologic malignancies. Our study elucidates the diagnostic performance of Risk of Ovarian Malignancy Algorithm (ROMA), Human epididymis secretory protein 4 (HE4) and cancer antigen (CA125). To compare the diagnostic accuracy of ROMA, HE-4 and CA125 in the early diagnosis and screening of Epithelial Ovarian Cancer. Literature search in electronic databases such as Medicine: MEDLINE (through PUBMED interface), EMBASE, Google Scholar, Science Direct and Cochrane library from January 2011 to August 2020. Studies that evaluated the diagnostic measures of ROMA, HE4 and CA125 by using Chemilumincence immunoassay or electrochemiluminescence immunoassay (CLIA or ECLIA) as index tests. Using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). We included 32 studies in our meta-analysis. We calculated AUC by SROC, pooled estimated like sensitivity, specificity, likelihood ratio, diagnostic odds ratio (DOR), Tau square, Cochran Q through random effect analysis and meta-regression. Data was retrieved from 32 studies. The number of studies included for HE4, CA125 and ROMA tests was 25, 26 and 22 respectively. The patients with EOC were taken as cases, and women with benign ovarian mass were taken as control, which was 2233/5682, 2315/5875 and 2281/5068 respectively for the markers or algorithm. The pooled estimates of the markers or algorithm were sensitivity: ROMA (postmenopausal) (0.88, 95% CI 0.86–0.89) > ROMA (premenopausal) 0.80, 95% CI 0.78–0.83 > CA-125(0.84, 95% CI 0.82–0.85) > HE4 (0.73, 95% CI 0.71–0.75) specificity: HE4 (0.90, 95% CI 0.89–0.91) > ROMA (postmenopausal) (0.83, 95% CI 0.81–0.84) > ROMA (premenopausal) (0.80, 95% CI 0.79–0.82) > CA125 (0.73, 95%CI 0.72–0.74), Diagnostic odd’s ratio ROMA (postmenopausal) 44.04, 95% CI 31.27–62.03, ROMA (premenopausal)-18.93, 95% CI 13.04–27.48, CA-125-13.44, 95% CI 9.97–18.13, HE4-41.03, 95% CI 27.96–60.21 AUC(SE): ROMA (postmenopausal) 0.94(0.01), ROMA (premenopausal)-0.88(0.01), HE4 0.91(0.01), CA125-0.86(0.02) through bivariate random effects model considering the heterogeneity. Our study found ROMA as the best marker to differentiate EOC from benign ovarian masses with greater diagnostic accuracy as compared to HE4 and CA125 in postmenopausal women. In premenopausal women, HE4 is a promising predictor of Epithelial ovarian cancer; however, its utilisation requires further exploration. Our study elucidates the diagnostic performance of ROMA, HE4 and CA125 in EOC. ROMA is a promising diagnostic marker of Epithelial ovarian cancers in postmenopausal women, while HE4 is the best diagnostic predictor of EOC in the premenopausal group. Our study had only EOC patients as cases and those with benign ovarian masses as controls. Further, we considered the studies estimated using the markers by the same index test: CLIA or ECLIA. The good number of studies with strict inclusion criteria reduced bias because of the pooling of studies with different analytical methods, especially for HE4. We did not consider the studies published in foreign languages. Since a few studies were available for HE4 and CA125 in the premenopausal and postmenopausal group separately, data were inadequate for sub-group analysis. Further, we did not assess these markers' diagnostic efficiency stratified by the stage and type of tumour due to insufficient studies.

New Analytical Approach for the Alignment of Different HE4 Automated Immunometric Systems: An Italian Multicentric Study

“…According to previous studies, our results confirm the prominent role of HE4 in diagnosis of OC in post-menopausal women [ 29 ]. Recently, COVID-19 caused delays in diagnostic investigation, surgical procedures, and routine surveillance for all women.…”

Biomarker-Based Models for Preoperative Assessment of Adnexal Mass: A Multicenter Validation Study

“…The concurrent validation of ROMA-50 and CPH-I produced the most polarized results within the whole validation cohort: ROMA-50 had a c-index of 0.54, while CPH-I had one of 0.92. The poor performance of ROMA-50 was below expectations and below the reported ranges for ROMA and its variants [ 19 , 23 , 27 ]. We think that the unsatisfactory performance of ROMA is due to the fact that the dichotomous variable menopause (which summarizes e.g., early postmenopausal and octogenarian women) is less informative compared to age, which reflects the continuous accumulation of cancerogenic defects and mutations together with non-oncologic comorbidities throughout the lifespan.…”

“…Circulating CA125 levels increase with tumor burden, but—conversely—they do not exceed the usual cutoff of 35 U/mL at 50% of early OC [ 15 ]. The sensitivity of CA125 has been reported at 0.78–0.86, the specificity at 0.57–0.82, the positive predictive value (PPV) at 0.50–0.68 and the negative predictive value (NPV) at 0.9–0.95 [ 11 , 12 , 16 , 17 , 18 , 19 ]. Amongst a further 200 investigated biomarkers, the cancer antigens CA 72.4, CA 15.3, CA 19.9 and HE4 have been considered the most informative for the evaluation of adnexal mass [ 4 , 13 , 20 ].…”

“…In their registration trials, both the ROMA and OVERA predicted pelvic malignancy with 0.91–0.94 sensitivity, 0.69–0.74 specificity and 0.97–0.99 NPV [ 5 ]. ROMA, OVA1 and OVERA have been cleared by the US Food and Drug Administration (FDA) for diagnosing suspicious adnexal mass, but not for screening [ 19 , 23 ]. A promising modification of ROMA is the Copenhagen Index (CPH-I), calculated from CA125, HE4 and patient age, which seems to be equal or superior to ROMA, and does not require knowledge of the patient’s menopausal status [ 24 , 25 , 26 , 27 ].…”

Comparison of HE4, CA125, ROMA and CPH-I for Preoperative Assessment of Adnexal Tumors

“…This finding is supported by previous studies that suggest that in premenopausal women ROMA does not seem to have any advantage over the use of HE4 [ 30 , 31 , 32 ]. A recent meta-analysis retrieving data from 32 studies showed higher AUC and specificity of HE4 in premenopausal women, compared to CA125 and ROMA [ 33 ]. Other authors report higher AUCs for CPH-I, when compared to ROMA and HE4 in premenopausal women [ 23 ].…”