For the past 50 years, ovarian cancer has remained the leading cause of gynecologic cancer mortality in the United States. Although advances in surgical technique, postoperative care, and chemotherapy have resulted in a modest improvement in 5-year survival, most patients continue to present with advanced-stage disease in which the cure rate is low and treatment cost is high. This year, more than 14,000 deaths from ovarian cancer will be reported in the United States,1 making it the fifth leading cause of female cancer mortality. Women with a known genetic predisposition for ovarian cancer often are advised to undergo risk-reducing salpingo-oophorectomy after completion of childbearing.2 However, risk-reducing salpingo-oophorectomy has been associated with premature menopause,3 cardiovascular disease,4 osteoporosis,5 and decreased cognitive function.6 These complications are reduced by hormone therapy, but endocrine-related symptoms often persist above premenopausal levels.7 With the recognition that many or most ovarian cancers actually arise in the fallopian tube, opportunistic salpingectomy has been more recently advocated as a risk-reducing strategy but with less supportive data.2 Because early-stage ovarian cancer is highly curable, screening at-risk women has been investigated by several different approaches as a method to increase earlier diagnosis and improve patient survival. Ovarian cancer screening has been reported to decrease stage at detection,8–12 but its effect on overall survival is unclear.13,14
The University of Kentucky Ovarian Cancer Screening Trial was initiated in 1987 to determine the effect of annual transvaginal ultrasonography on stage at detection and ovarian cancer mortality.15 Since that time, free screening has been provided to more than 46,000 women. The following investigation documents stage at detection and long-term survival of patients with type I and type II epithelial ovarian cancer detected by screening in the University of Kentucky Ovarian Cancer Screening Trial.
MATERIALS AND METHODS
Women who enrolled in the University of Kentucky Ovarian Cancer Screening Trial from January 1987 to June 2017 were evaluated. This prospective cohort trial was approved by the University of Kentucky institutional review board for human studies. Eligibility criteria included 1) all asymptomatic women aged 50 years or older and 2) asymptomatic women aged 25 years or older with a documented family history of ovarian cancer in at least one primary or secondary relative. Genetic testing was not performed routinely as part of this trial. Before study entry, all study participants completed a questionnaire that included medical history, surgical history, menopausal status, hormonal use, and family history of cancer. Menopause was defined as the absence of menses for 12 months. Women with a known ovarian tumor or a personal history of ovarian cancer were excluded from this investigation.
After informed consent, each patient underwent screening according to the algorithm illustrated in Figure 1. Since 2015, transvaginal ultrasonography and color Doppler have been performed using General Electric Voluson P8 units with a 4- to 11-mHz vaginal probe. All ultrasound images were reviewed by at least one of the authors. At each screen, both ovaries were measured in three dimensions. Ovarian volume was calculated using the prolate ellipsoid formula (length×width×height×0.523). All screening information was entered into a database on a local network. Criteria for abnormality included an ovarian volume greater than 20 cm3 for premenopausal women and greater than 10 cm3 for postmenopausal women. These values were used because they were greater than 2 SDs above the mean volume of normal ovaries in premenopausal and postmenopausal women.15,16 In addition, any cystic ovarian tumor with a solid or papillary projection into its lumen was considered abnormal. Women who had a normal screen were scheduled to return in 12 months for a repeat screen. Women who had an abnormal screen underwent a repeat ultrasound examination in 4–6 weeks. Women with an abnormal second screen had a serum CA 125 determination, tumor morphology indexing, and Doppler flow ultrasonography. Morphology indexing was performed according to the classification of Ueland et al.17 Each tumor was given a score from 1 to 10 according to increasing morphologic complexity and volume. During the last 10 years of this trial, women with unilocular cystic ovarian tumors or septated cystic tumors that measured less than 10 cm in greatest dimension and a normal serum CA 125 level have been followed without surgery by repeat ultrasonography. Women with a persisting solid or complex ovarian tumor or women with a cystic ovarian tumor and an elevated serum CA 125 level were advised to undergo laparoscopic tumor removal as the initial step in operative evaluation.
Patients with ovarian cancer on frozen section underwent immediate staging or tumor debulking for those with obvious metastatic disease. Tumors were classified histologically according to the World Health Organization system and were staged according to the International Federation of Gynecology and Obstetrics system. Ovarian cancers, both in the screening and control groups, were divided into type I and type II tumors according to the criteria of Kurman and Shih.18,19 Mucinous carcinoma, clear cell carcinoma, and low-grade serous and endometrioid carcinoma were classified as type I tumors, and high-grade serous and endometrioid carcinoma, undifferentiated carcinoma, and carcinosarcoma were designated as type II tumors. After surgery, patients were treated according to the cell type, histologic differentiation, and stage of each tumor, usually with six cycles of platinum+taxane chemotherapy. Patients with ovarian cancer were followed at monthly intervals during treatment, every 3 months for 2 years after completion of treatment, and every 6 months thereafter. Follow-up data on all patients were coordinated with the American Cancer Society, the University of Kentucky Tumor Registry, the Kentucky Cancer Registry, and the Kentucky State Department of Vital Statistics. Participants were required to provide a Social Security number, and annual searches of the Social Security Death Index were performed. Cause of death was confirmed by analysis of relevant clinical records and state death certificates.
Unscreened women with clinically detected epithelial ovarian cancer referred to the University of Kentucky-Markey Cancer Center for treatment from 1995 to 2017 served as the control group for this investigation. The time period for evaluation of the control group was chosen because after 1995, patients with ovarian cancer treated at this institution all underwent maximal tumor cytoreduction at the time of surgical staging, received combination platinum+taxane chemotherapy, and were treated by gynecologic oncologists using the same evaluation algorithms and treatment protocols.
Proportions were compared using χ2 statistics. Statistical significance was determined at the .05 level. Survival was estimated using the Kaplan-Meier method with differences tested using the log-rank test and interactive factors tested using the Cox regression proportional hazards model. Unscreened controls were examined with and without adjustments to frequencies in the screened group using auxiliary variables of age and family history, as described by Bethlehem.20 Adjustment resulted in less than 1% differences between screened and unscreened distributions.
A total of 46,101 women enrolled in the University of Kentucky Ovarian Cancer Screening Trial from January 1987 to June 2017. A family history of ovarian cancer was documented in 10,680 (23.2%) of these women and 20,195 (43.8%) had a family history of breast cancer. Women enrolled in this study underwent a total of 298,418 scans (mean 6.5 scans per participant). One or both ovaries were visualized in 246,275 scans (82.4%). Ultrasonographically undetectable ovaries were considered normal for purposes of this investigation.
A total of 699 women (1.5%) with persisting ovarian tumors on transvaginal ultrasonography underwent surgery (Fig. 2). Complications were graded according to the Clavien-Dindo Classification21 with grade 1 complications being minor and grade 4 most severe. These results were reported by Baldwin et al22 and were updated to the present. Nineteen of the 109 patients (17.4%) undergoing surgery for an ovarian malignancy experienced a surgical complication, including four grade 4 complications. Thirty-nine of 590 women (6.6%) undergoing surgery for a benign ovarian tumor detected by screening (false-positive) experienced a postoperative complication; all were minor (grade 1) except one reoperation for a small bowel obstruction after laparoscopy.
Seventy-one women with invasive epithelial ovarian cancer were detected by screening. Although 17 ovarian tumors of low malignant potential, six patients with nonepithelial ovarian malignances, and 15 patients with cancers metastatic to the ovary were also detected by screening (Box 1), these were not included in the survival analysis but are considered true-positive results as in other studies. The summarized statistical results of our screening protocol for the entire 30-year duration are shown in Table 1. The overall incidence rate for ovarian cancer in the Kentucky screening population (including true-positive and false-negative cases) was 271 per 100,000, which is higher than the ovarian cancer incidence adjusted to the standard population (10.4/100,000).23 The sensitivity of transvaginal ultrasound screening in our higher risk population was 87.2% and the specificity was 98.7%. The positive predictive value of an abnormal screen was 15.6%, and the negative predictive value of a normal screen was 99.97%. After 2014, the positive predictive value increased to 25% (P<.001) when the screening algorithm was changed to not recommend surgery in women with unilocular cystic or septated cystic ovarian tumors less than 10 cm diameter.24
Histologic Findings in Patients With Persistently Abnormal Screens (n=699)
Epithelial ovarian cancer: 71
Nonepithelial ovarian cancer: 6
Epithelial ovarian tumor of low malignant potential: 17
Metastatic cancer to ovary: 15
- Appendix: 4
- Primary peritoneum: 5
- Breast: 1
- Endometrium: 1
- Extrauterine myxoid: 1
- Colon: 1
- Bladder: 2
Serous cystadenoma: 270
Mucinous cystadenoma: 35
Cystic teratoma: 31
Fibroma, thecoma, Brenner tumor: 65
Hydrosalpinx, paratubal cyst: 40
Hemorrhagic cyst, other: 75
The median age of the 71 women with epithelial ovarian cancer detected by screening was 66 years (range 36–86 years). An abnormality in ovarian morphology or volume was detected on the first screen in 16 patients (23%) and on subsequent screens in 55 patients (77%). All ovarian malignancies were solid or complex (both solid and cystic components) except two with cystic morphology and a thickened cyst wall. The mean morphology index score of ovarian malignancies was 6.0 (median 5, range 1–10) vs 3.7 (median 4, range 0–10) for benign ovarian tumors (P<.001). Seventeen percent of women with invasive ovarian cancer detected by screening reported a family history of ovarian cancer with three women diagnosed at younger than 50 years old. At the time of surgery, 30 of the 71 women (42%) with epithelial ovarian cancer detected by screening had stage I disease, 15 (21%) had stage II disease, and 26 (37%) had stage III disease. In contrast, 276 of 921 (30%) unscreened women with clinically detected epithelial ovarian cancer had stage I or stage II disease at the time of diagnosis (P<.001). Twenty-six women (37%) in the screening group had stage III ovarian cancer at the time of detection as compared with 70% of women in the unscreened group with stage III or IV disease at diagnosis (P<.001). In addition, there was a substage shift within stage III ovarian cancer in the screening group. Twelve of the 26 women with stage III ovarian cancers detected by screening (46%) had IIIA or IIIB tumors, whereas 84% of unscreened women with stage III ovarian cancer presented with stage IIIC disease (P<.001). There were no cases of stage IV ovarian cancer detected in women undergoing screening.
Serum CA 125 level was elevated (greater than 35 units/mL) in 39 of 71 women (55%) with screen-detected ovarian cancers. CA 125 level was abnormal in 18 of 45 women (40%) with stage I or stage II ovarian cancer and in 21 of 26 women (81%) with stage III disease. Three women did not have a preoperative CA 125 determination.
The cell types of screen-detected ovarian cancer are illustrated in Table 2. Nineteen women (27%) had type I ovarian cancers and 52 women (73%) had type II ovarian cancers. Seventy-eight percent of women with type I tumors were detected with stage I disease compared with 29% of women with type II tumors.
Patients with invasive ovarian cancer all underwent comprehensive surgical staging and cytoreduction as indicated. Complete cytoreduction (no visible residual disease) was achieved in all patients with stage I–IIIB disease. Eighty-nine percent of patients with stage IIIC disease were cytoreduced to less than 1 cm residual disease, and 63% had no visible residual disease. Three patients with stage IA grade 1 endometrioid carcinoma were treated by surgery alone, and the remaining patients received adjuvant chemotherapy. For the past 20 years of this investigation, patients requiring chemotherapy have typically received six cycles of intravenous carboplatin (AUC 6) and paclitaxel (175 mg/m2) every 3 weeks as their initial postsurgery treatment regimen.
After therapy, patients with screen-detected ovarian cancers were followed from 0.8 to 27.2 years (mean 7.8 years, median 6.2 years) and none were lost to follow-up. To date, 17 patients with screen-detected ovarian cancer have died of ovarian cancer, and 13 have died of other causes with no evidence of disease. Forty-one patients are alive. One of 30 patients (3%) with stage I disease, 5 of 15 patients (33%) with stage II disease, and 10 of 26 (38%) with stage III disease have died of ovarian cancer. During this trial, 16 women developed interval ovarian cancer within 1 year of a normal screen (false-negative), and 13 of them have died of disease. These women generally had type II tumors with minimal ovarian enlargement on transvaginal ultrasonography and were diagnosed 6–12 months after a normal scan. The 5-year and 10-year survival of these interval cases was 50±12% and 15±12%.
The disease-specific survival of women with invasive epithelial ovarian cancer detected by screening was 86±4% at 5 years and 68±7% at 10 years (Fig. 3) vs 45±2% at 5 years and 31±2% at 10 years in the 931 unscreened women whose ovarian cancer was clinically detected (P<.001). These women all were surgically staged and treated by the same surgery and chemotherapy protocols as those women detected by screening. When the interval (false-negative) cases are included, the 5-year disease-specific survival of women with ovarian cancer in the screening group is 79±4%, which remains significantly (P<.001) higher than that of women who did not have screening.
The disease-specific survival of women with screen-detected type I ovarian malignancies (Fig. 4) was 83±9% at 5 and 10 years vs 69±3% and 58±4% in women with clinically detected type I ovarian malignancies (P<.05). Seventy-nine percent of women with screen-detected type I tumors had stage I or II disease. The disease-specific survival of women with screen-detected type II malignancies was 88±5% at 5 years and 63±9% at 10 years vs 34±2% at 5 years and 18±2% at 10 years in women with clinically detected type II ovarian malignancies (P<.001). Fifty-eight percent of women with screen-detected type II tumors had stage I or II disease.
The prognostic importance of stage at detection is illustrated in Figure 5. The 5-year and 10-year disease-specific survival of women with screen-detected stage I and II ovarian cancer was 93±4% and 81±7% vs 75±9% and 46±13% in women with screen-detected stage III disease. Therefore, lowering stage at detection from stage III ovarian cancer to stage I or II ovarian cancer was associated with a 10-year survival advantage of 35%.
The cost-effectiveness of screening for ovarian cancer in this trial is summarized in Box 2. Ovarian screening reduced the 10-year mortality by 37% and produced 416 life years gained. The total screening cost per life year gained was $40,731 when using a very conservative estimate of $56 per transvaginal ultrasonography and acknowledging that other expenses too will vary widely across centers.
Cost-Effectiveness of Ovarian Cancer Screening (N=46,101)
No. of screens: 298,418
No. of true-positive results: 109
No. of false-positive results: 327
Surgical cost/false-positive case: $7,954
Total no. of false-positive cases assuming PPV of 25%: 327
Total screening cost: $19,354,144
Cost advantage of treating earlier detected screening cases: $2,409,880
Net screening cost: $16,944,264
10-y survival screen-detected cases: 68%
10-y survival clinically detected cases: 34%
Patient lives saved: 26 of 71 patients
Mean age screen-detected women: 65 y
Mean age female life expectancy, United States: 81 y
Mean life years gained/case: 16
Total life years gained: 416
Cost/total life year gained: $16,944,264/416 life year gained = $40,731
PPV, positive predictive value.
Ovarian cancer screening can lead to earlier detection.9–12 Forty-eight percent of invasive ovarian cancers detected by multimodal screening in the United Kingdom Collaborative Trial of Ovarian Cancer Screening had stage I–II disease compared with 24% in the unscreened control group (P<.05).11,14 Likewise, multimodal screening in women estimated to have a lifetime risk of ovarian cancer 10% or greater was recently reported to lead to a significant decrease in stage at detection in the United Kingdom Familial Ovarian Cancer Screening Study.25 In the ultrasonography arm of the Prostate, Lung, Colorectal, and Ovarian Trial, 72% of detected cancers were stage I or II, but 74% of the biomarker-detected cancers in this trial were stage IIIC or IV, and there was no overall decrease in stage at detection in the screened group.26 In the present investigation, annual ultrasound screening was associated with a reduction in stage at detection. Sixty-three percent of women whose invasive ovarian cancer was detected by screening had stage I or II disease as opposed to 30% in unscreened women from the same geographic area diagnosed clinically during the same time period. That there was a substage shift within stage III in the screening group also is important because there is a 5-year survival advantage of 20% in patients with stage IIIA compared with stage IIIC disease in the era of platinum+taxane chemotherapy.27
Screening was more effective in detecting early-stage type I ovarian cancer than early-stage type II ovarian cancer. Seventy-nine percent of type I ovarian cancers were detected with early-stage disease compared with 58% of type II tumors. This is consistent with molecular genetic findings confirming that only 40% of type II tumors originate from ovarian surface epithelium.28 The higher 5-year, 10-year, and 20-year survivals observed in patients with type I tumors compared with those with type II tumors are related directly to this stage distribution. It is interesting that 12 of the 16 women who developed ovarian cancer within 12 months of a negative screen (false-negative) had type II tumors, confirming the rapid progression of these tumors and the short preclinical phase during which screening could lead to earlier detection.19
One of the concerns about transvaginal ultrasound screening for ovarian cancer is its low positive predictive value. Although the sensitivity of transvaginal ultrasonography in detecting an ovarian abnormality is high, it has been unreliable in differentiating benign from malignant ovarian tumors. In the Prostate, Lung, Colorectal, and Ovarian Trial, for example, 19.5 surgeries were performed to detect one ovarian cancer (positive predictive value 5.1%).26 Ultrasound assessment of the risk of malignancy in ovarian tumors is now more accurate because of published data correlating risk of malignancy with tumor morphology.29 Unilocular and septated ovarian cysts less than 10 cm in diameter have been shown to have minimal neoplastic risk and since 2009 have been followed ultrasonographically without surgery.30,31 Also, there is quantitative evidence that malignant ovarian tumors become morphologically more complex with time, whereas benign tumors remain the same or decrease in complexity.32 As a result, the positive predictive value of serial screening in the University of Kentucky Ovarian Cancer Screening Trial increased to 25% when used prospectively from 2014 to the present. The screening protocol in this trial also benefitted from the relatively high prevalence of ovarian cancer in the screened population (271/100,000), which was significantly higher than that of the general population. This allowed more cases of ovarian cancer to be detected and reaffirms the recommendation that screening should be offered only to moderately high-risk populations of women with a lifetime risk of ovarian cancer of 3–10%.2
A related concern is that screen-positive women whose ovarian tumors are benign at the time of surgery (false-positive) might experience significant postoperative morbidity. In the United Kingdom Collaborative Trial of Ovarian Cancer Screening multimodal screening arm, only 15 of 488 screen-positive women with benign ovarian tumors at surgery (3.1%) experienced a postoperative complication, and 80% of these were minor.14 In the present trial, laparoscopy with tumor removal was the standard diagnostic approach for screen-detected ovarian tumors, and women with benign disease usually received no additional surgery. Surgical complications occurred in only 6.6% of these cases, and 97% of these complications were minor. These data confirm that the frequency of serious complications in women undergoing diagnostic surgery for a benign ovarian tumor detected by screening is extremely low.
A fundamental question that remains unanswered is the effect of screening on ovarian cancer mortality. Both the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the United Kingdom Collaborative Trial of Ovarian Cancer Screening were prospective randomized trials designed to answer this question. Screening was not associated with an increase in the overall survival of patients with ovarian cancer in the Prostate, Lung, Colorectal, and Ovarian Trial.13 However, there was no standard evaluation algorithm for screen-detected ovarian tumors and no uniform treatment protocol for newly diagnosed ovarian cancers in this trial. As a result, there was significant variation in the detection–treatment interval and type of treatment in both the screening and control arms of this trial. In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, multimodal screening was associated with a decrease in stage at detection and a significant reduction in ovarian cancer mortality when prevalent cases were excluded.14 In the present trial, ovarian cancer was detected at an earlier stage by screening, which, in turn, resulted in significantly higher survival of patients with screen-detected cancers when compared with those with clinically detected cancers. The 10-year ovarian cancer mortality was reduced in women receiving screening by 31% and produced 416 life years gained at a cost of $40,851 per life year gained. This is similar to that reported previously for multimodal screening when applied to the U.K.33 and U.S. populations.34
The present investigation provides long-term follow-up data on a large number of asymptomatic women undergoing transvaginal ultrasound screening for ovarian cancer who had a greater than 20-fold higher prevalence of disease than the standard population. It documents that screening is safe and well accepted, and that women undergoing diagnostic surgery for a screen-detected ovarian tumor experience few significant complications. In the present trial, women were not prospectively randomly assigned to a nonscreening arm. However, the control population consisted of women from the same geographic area, whose ovarian cancers were detected clinically during the same time period and who were then referred to the University of Kentucky-Markey Cancer Center. Women whose ovarian cancers were screen-detected or clinically detected were then evaluated and treated by the same gynecologic oncologists using the same evaluation algorithms and treatment protocols.
The findings of this study support the concept that a major predictor of ovarian cancer survival is stage at detection. The 10-year survival of women whose ovarian cancer was detected at an early stage (I or II) was 35% higher than that of women diagnosed with stage III cancer. Likewise, the survival of women with biologically aggressive type II ovarian cancer was excellent, provided they were detected with early-stage disease. Without early detection, it is likely that many of these tumors would have advanced significantly before clinical diagnosis, making the chance of cure unlikely even with optimal treatment.
Additional research is necessary to identify high-risk populations who will benefit most from screening. Menon et al2 have suggested that screening should be preferentially offered to women with a lifetime ovarian cancer risk of 3–10%, whereas women at greater than 10% risk should consider risk-reducing surgery. Recent data suggests that BRCA mutations, other germline mutations, and common variant risk alleles may be responsible for up to 30% of high-grade serous ovarian cancers.35 With advances in genetic testing, including more affordable next-generation sequencing,36 it soon may be feasible to identify populations of women who will benefit most from more focused screening.
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