28Tubo-Ovarian Cancer Screening
SCREENING TEST
A good screening test is both sensitive (high probability of detecting disease) as well as specific (high probability that those with disease will be identified). An ideal screening test has a sensitivity of 100% and a specificity of 95%. Screening tests are typically not designed to diagnose disease; rather, they identify subjects who need further diagnostic tests or procedures. A positive predictive value (PPV) of 10% or greater is the goal of any screening test. This means that 1 diagnosis per 10 interventions is needed for the test to be considered worthwhile.
CA-125
CA-125 alone has a sensitivity of 83%; specificity of 59%; PPV of 16%; and NPV of 97%.
HE4
HE4 alone has a sensitivity of 78%; specificity of 95%; PPV of 80%; and NPV of 99%. It has no sensitivity for borderline tumors.
RISK OF MALIGNANCY INDEX
• The risk of malignancy index (RMI) incorporates ultrasound findings with menopausal status (M) and the CA-125 level. It is written as: RMI = U × M × CA-125. A score of either 0, 1 or 3 is given to the U. U=0 for an ultrasound with no features of malignancy. U = 1 for an ultrasound score of 1. U = 3 for an ultrasound score of 2 to 5. A score of either 1 or 3 is given for menopausal status. M = 1 for premenopausal women or M = 3 for postmenopausal women (19).
• On ultrasound, 1 point is given for each of the following morphologies: multiloculation, solid components, bilaterality, ascites, or intra-abdominal metastasis. The stated sensitivity is 81%, specificity is 85%, PPV is 48%, and NPV is 96%. If the calculated level of RMI is greater than 200, referral to a gynecologic oncologist is recommended.
MORPHOLOGY INDEX
• The Ueland morphology index (MI) assesses ovarian tumors based on tumor volume and wall structure. When the MI is less than 5, most adnexal masses are found to be benign with a NPV of 99%. If the MI is greater than 5, the PPV has been stated at 40% (1).
• The Kentucky University Algorithm has identified women at higher risk for ovarian cancer. A baseline ultrasound is obtained. If it is abnormal, it is repeated within 6 weeks. If the repeat ultrasound is found to still be abnormal, a CA-125 is drawn and the MI is calculated. The stated sensitivity is 85%, the specificity is 98%, the PPV is 14%, and the NPV is 99%. Disease was found at an earlier stage (i.e., stage migration) if there was strict adherence to these guidelines. 64% of cancers were found at Stage I (2).
RISK OF OVARIAN MALIGNANCY ALGORITHM
• The combination test of HE4 and CA-125 is called the predictive probability algorithm or risk of ovarian malignancy algorithm (ROMA). This predictive algorithm is calculated for premenopausal and postmenopausal women separately, using the following equations. To calculate the algorithm the assay values obtained from the HE4 EIA and CA-125 II assays are inserted into the applicable equation.
Premenopausal woman:
Predictive index (PI) = −12.0 + 2.38 × LN (HE4) + 0.0626 × LN (CA-125)
Postmenopausal woman:
PI = −8.09 + 1.04 × LN (HE4) + 0.732 × LN (CA-125)
• To calculate the ROMA value (the predictive probability), insert the calculated value for the PI into the following equation: ROMA value % = exp(PI)/(1 + exp(PI)) × 100
The following cut-off points were used in order to provide a specificity level of 75%:
• Premenopausal women:
ROMA value ≥13.1% = High risk of finding epithelial ovarian cancer
ROMA value <13.1% = Low risk of finding epithelial ovarian cancer
• Postmenopausal women:
ROMA value ≥27.7% = High risk of finding epithelial ovarian cancer
ROMA value <27.7% = Low risk of finding epithelial ovarian cancer
This test is stated to have a sensitivity of 94%; specificity of 75%; PPV of 58%; and NPV of 97%.
RISK OF OVARIAN CANCER ALGORITHM (ROCA)
This test represents the slope of serial CA-125 levels drawn over a period of time and correlated with patient age. If there is greater than 1% change in the slope of the line, a transvaginal ultrasound (TVUS) is recommended. The UK ROCA study showed a PPV of 19% and a specificity of 99.8%.
COPENHAGEN INDEX
Copenhagen Index (CPH-I) uses the following variables: serum HE4, serum CA-125 and patient age instead of menopausal status, omitting ultrasound characteristics. Comparison of CPH-I, ROMA, and RMI demonstrated an AUC of 0.951, 0.953, and 0.935, respectively. Using a sensitivity at 95%, the specificities for CPH-I, ROMA, and RMI in the validation cohort were 67.3%, 70.7%, and 69.5%, respectively, in the validation study. The coefficients are CPH-I = −14.0647 + 1.0649 × log2(HE4) + 0.6050 × log2(CA-125) + 0.2672 × age/10. The predicted probability is = e(CPH-I)/(1 + e(CPH-I)) (3).
OVA-1 TEST
The OVA-1 test utilizes five well-established biomarkers: prealbumin, apolipoprotein A-1, beta2-microglobulin, transferrin, and CA-125. A proprietary algorithm is 30used to determine the likelihood of malignancy in women with a pelvic mass for whom surgery is planned. The sensitivity is stated to be 92.5%, with a specificity of 42.8%, PPV of 42.3%, and NPV of 92.7%. It is important to remember not to perform this test if the patient has a rheumatoid factor ≥ 250 IU/L or has a triglyceride level >450 mg/dL.
OVARIAN CANCER SYMPTOM INDEX
The ovarian cancer symptom index (SI) associates specific symptoms with ovarian cancer. These symptoms are pelvic/abdominal pain, urinary urgency/frequency, increased abdominal size/bloating, and difficulty eating/feeling full. These symptoms become significant when present for less than 1 year and when they occur greater than 12 days/month. The overall sensitivity was 64% and specificity 88%. For women who are found to have early-stage disease, the sensitivity is stated to be 56.7%, and for women with advanced-stage disease it is 79.5%. When age stratified, the specificity is stated at 90% for women greater than 50 years old and 86.7% for women less than 50 years old (4).
• The SI in combination with a CA-125 has also been used to risk stratify adnexal masses. The combination of CA-125 and the SI has been shown to identify 89.3% of women with cancer, 80.6% of early-stage cancers, and 95.1% of late-stage cancers. The false-positive rate was 11.8% (5).
• The SI in combination with both CA-125 and HE4 has been found to have a sensitivity of 95% and specificity of 80%. If any two of the three tests were positive, a sensitivity of 84% and specificity of 98.5% were found. When all three tests were used, the specificity was 98.5% and the sensitivity was 58% (6).
THE UK COLLABORATIVE TRIAL OF OVARIAN CANCER SCREENING
The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) evaluated 202,638 women aged 50 to 74 years. They were randomized in a 2:1:1 ratio to: no treatment (101,299), annual screening with TVUS (50,623), and annual CA-125 (interpreted as a ROCA) with TVUS as a second-line test (50,624) (designated multimodal screening, MMS). MMS screening was performed using the ROCA algorithm including serial CA-125 level and ultrasound risk factors to include size, volume, and complexity of ovarian cyst. If ultrasound was abnormal, a repeat ultrasound was scheduled either at 3 months or 6 weeks depending on complexity assessment. The sensitivity, specificity, and positive predictive values for all primary ovarian type cancers in 2009 were 89.4%, 99.8%, and 43.3% for MMS, and 84.9%, 98.2%, and 5.3% for TVUS screening. In the MMS arm, 2.9 surgeries were needed per cancer detected, compared to 35.2 in the TVUS group. In the follow-up study published in 2015, the primary outcome was death due to tubo-ovarian cancer. The median follow-up was 11.1 years, and ovarian cancers were diagnosed in 630 (no screening), in 338 (MMS), and 314 (TVUS) women. The mortality reduction over years 0 to 14 using the Cox model was 15% with MMS, and 11% with TVUS, which were not significant compared to no screening. This mortality reduction was made up of an 8% relative reduction in mortality during years 0 to 7 (NS), and 23% relative reduction in mortality during years 7 to 14 in the MMS versus no screening, and of 2% (NS) and 21%, respectively, in the TVUS group versus the no screening group. The total number 31of surgeries was not reported but 488 benign surgical outcomes (false positives) were documented in the MMS group, 1,634 false positive surgeries in the TVUS group, with surgical complications of 3.1% in the MMS group and 3.5% in the TVUS group. Prevalent cases of cancer were also removed from the analysis. Additionally, 792 women in the no screening group, 466 in the MMS group, and 441 in the ultrasound group had a BSO outside of the trial, again confounding the results. The overall ratio of women who had surgery resulting in benign pathology to cancer was 1:2 (792/645) in the no screening group, 2:7 (954:354) in the MMS group, and 6:4 (2075:324) in the TVUS group. There was no total number of women reported who screened positive so we don’t know how many surgeries were needed for false-positive screens (7,8).
THE PROSTATE, LUNG, COLON, AND OVARIAN (PLCO) CANCER TRIAL
This study compared CA-125 levels and ultrasound imaging versus observation in 78,216 women aged 55 to 74 with annual TVUS for 4 years and CA-125 for 6 years. 42 of 61 ovarian cancers were found, but 28 (67%) of these were advanced stage. The PPV was 1.1%; the number needed to treat was 20:1. 15% of patients had serious complications related to surgery. There was no evidence of stage migration. Additional data discovered in this trial revealed that 14% of postmenopausal women had simple ovarian cysts, at an 8% incidence; and 32% of these cysts spontaneously regressed. A 15-year follow-up reviewed mortality benefit between arms. Again, 39,105 women were randomized to the intervention arm and 39,111 were in the usual care arm. Median follow-up was 14.7 years in each arm and maximum follow-up 19.2 years in each arm. A total of 187 (intervention) and 176 (usual care) deaths from ovarian cancer were observed, for a risk ratio of 1.06 (95% CI: 0.87–1.30). Risk ratios were similar for study years 0 to 7 (RR = 1.04), 7 to 14 (RR = 1.06) and over 14 years (RR = 1.09). The risk ratio for all-cause mortality was 1.01 (95% CI: 0.97–1.05). Ovarian cancer specific survival was not significantly different across trial arms (p = 0.16). Conclusion: extended follow-up of women in the PLCO study indicated no mortality benefit from screening (9,10).
JAPAN SCREENING STUDY
Shizuoka Cohort Study of Ovarian Cancer Screening: this was a prospective randomized controlled trial of ovarian cancer screening. Asymptomatic postmenopausal women were randomly assigned between 1985 and 1999 to an intervention group (n = 41,688) or a control group (n = 40,799) in a 1:1 ratio. The mean follow-up was 9.2 years. Women in the intervention group had annual pelvic ultrasound and serum CA-125. Women with abnormal ultrasound findings and/or raised CA-125 values were referred for surgical investigation by a gynecological oncologist. 27 cancers were detected in the 41,688 screened women. Eight more cancers were diagnosed outside the screening program. Detection rates of ovarian cancer were 0.31 per 1,000 at the prevalent screen and 0.38 to 0.74 per 1,000 at subsequent screens; they increased with successive screening rounds. Among the 40,779 control women, 32 women developed ovarian cancer. The proportion of stage I ovarian cancer was higher in the screened group (63%) than in the control group (38%), which did not reach statistical significance (p = 0.2285) (11).
32SERIAL ULTRASOUND OF OVARIAN ABNORMALITIES
In a prospective TVUS study, 39,337 women were included. Ovarian masses were categorized into: (a) normal, (b) simple unilocular cysts, (c) cysts with septations uni- and multicloculated, (d) cysts with solid areas, and (e) solid masses. Septated complex masses without solid areas or papillary projections had a 40% spontaneous resolution rate with a mean time to resolution of 12 months. Indications for surgical evaluation in this screened population were complexity of abnormality increased to cystic with solid area or mostly solid; an increase in volume greater than 50 cm3 associated with constant or increasing complexity; or if new reported regional pain occurred after a second abnormal ultrasound. Resolution of ovarian masses did occur when followed serially. Resolution by category: unilocular cyst(s) 32.8% resolved at a mean of 55.6 weeks; cyst(s) with septation(s) 43.9% resolved at a mean of 53.0 weeks; cyst(s) with solid area(s) 76.5% resolved at a mean of 7.8 weeks; solid mass 80.6 resolved at a mean of 8.7 weeks. Low risk = unilocular and cysts with septations. High risk = cysts with solid area or solid mass. Thus it is helpful to not just have one ultrasound. Surgery was performed on 557 patients of 39,337 participants with 85 malignancies identified. The PPV for cancer rose from 8% to 25% by reducing false-positive results (12).
GOG 199
GOG 199 was a prospective study of women with confirmed genetic risk of ovarian cancer. At enrollment, women could choose to have ovarian cancer screening or undergo risk reducing surgery to include bilateral salpingoophorectomy. 2,605 women enrolled: there were 1,030 (40%) women in the surgical group and 1,575 (60%) elected to be in the screening group. The primary study outcomes was review of ovarian and breast cancer incidence, also including use of the Risk of Ovarian Cancer Algorithm. Nine neoplastic tubal lesions from 966 RRSO were identified, 8 of which occurred in BRCA mutation carriers (13,14).
OPPORTUNISTIC SALPINGECTOMY IN LOW-RISK WOMEN
No difference was found in ovarian function in premenopausal women undergoing hysterectomy versus hysterectomy and bilateral salpingectomy for benign disease. This was determined by assessment of anti-Müllerian hormone (AHM), follicle-stimulating hormone (FSH), antral follicle count, mean ovarian diameter, and peak systolic velocity on postoperative laboratories and imaging. There was no difference in operative time, postoperative stay, time to return to normal activity, and postoperative hemoglobin. Up to 700,000 women have a tubal ligation each year. This procedure can provide significant risk reduction opportunity (15).
OVARIAN CANCER RISK
Ovarian cancer risk after salpingectomy was evaluated in a population-based cohort study on women with prior surgery for benign indications compared to the unexposed population analyzed. The risk reductions for prior hysterectomy was hazard ratio (HR) = 0.79, sterilization HR = 0.72, hysterectomy with BSO HR = 0.06, unilateral salpingo-oophorectomy (USO) compared to 33BSO 0.35; all CI did not cross 1. BSO had a 50% lower chance of ovarian cancer than USO (16).
Women who have any abdominal surgery and have completed childbearing could have opportunistic bilateral salpingectomy/salpingo-oophorectomy as an adjunct to surgery (i.e., appendectomy, cholecystectomy, hysterectomy). 15% of ovarian cancers could be prevented annually by BSO at time of hysterectomy. A staged surgery to preserve ovarian function can be performed by bilateral salpingectomy: a Denmark study reduced the risk of ovarian type cancer by 42%, and a Swedish study by 65% with bilateral salpingectomy (20,21).
CHANGING CA-125 “NORMALS”
Future “screening” could focus on detection of advanced stage ovarian cancer when the disease burden is low enough that surgical debulking can primarily achieve no residual disease followed by intraperitoneal (IP) chemotherapy. By making low volume advanced stage ovarian cancer (stage IIIA/IIIB) the target, rather than stage I, the threshold for CA-125 could be raised to 70 U/mL. This would reduce the sensitivity for detecting all ovarian cancers from 75% to 70% but increase the specificity from 95% to 99%. The PPV of a CA-125 at 70 U/mL is then 5%. If the cut-off were raised to 100 U/mL, the sensitivity would be reduced to 60% but specificity increased to 99.9% and the PPV would increase to 31% (17).
SCREENING PELVIC EXAMINATION IN ADULT WOMEN
The American College of Physicians (ACP) recommends against performing screening pelvic examinations in asymptomatic nonpregnant adult women. They cite three cohort studies of 5,633 women including the negative results of PLCO assessing the diagnostic accuracy of a pelvic exam in asymptomatic women mean ages 51 to 58. Only four cases of ovarian cancer were identified in 1 year with a PPV 0% to 3.5%. Examination related “harms” were pain or discomfort ranging from 11% to 60%; and 10% to 80% for fear, embarrassment, or anxiety. Care should be taken with interpretation, of this study (18).
REFERENCES
1. Ueland FR, DePriest PD, Pavlik EJ, et al. Preoperative differentiation of malignant from benign ovarian tumors: the efficacy of morphology indexing and Doppler flow sonography. Gynecol Oncol. 2003;91(1):46-50.
2. van Nagell JR Jr, Miller RW, DeSimone CP, et al. Long-term survival of women with epithelial ovarian cancer detected by ultrasonographic screening. Obstet Gynecol. 2011;118(6):1212-1221.
3. Karlsen MA, Høgdall EV, Christensen IJ et al. A novel diagnostic index combining HE4, CA125 and age may improve triage of women with suspected ovarian cancer – an international multicenter study in women with an ovarian mass. Gynecol Oncol. 2015 Sep;138(3):640-646.
4. Goff BA, Mandel LS, Drescher CW, et al. Development of an ovarian cancer symptom index: possibilities for earlier detection. Cancer. 2007;109(2):221-227.
5. Andersen MR, Goff BA, Lowe KA, et al. Combining a symptoms index with CA125 to improve detection of ovarian cancer. Cancer. 2008;113(3):484-489.
6. Andersen MR, Goff BA, Lowe KA, et al. Use of a symptom index, CA125, and HE4 to predict ovarian cancer. Gynecol Oncol. 2010;116(3):378-383.
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