Obstetrics & Gynecology:
Long-Term Survival of Women With Epithelial Ovarian Cancer Detected by Ultrasonographic Screening
van Nagell, John Rensselaer Jr MD; Miller, Rachel Ware MD; DeSimone, Christopher P. MD; Ueland, Frederick R. MD; Podzielinski, Iwona MD; Goodrich, Scott T. MD; Elder, Jeff W. MD; Huang, Bin PhD; Kryscio, Richard J. PhD; Pavlik, Edward John PhD
From the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, and the Department of Statistics, the University of Kentucky Chandler Medical Center-Markey Cancer Center, Lexington, Kentucky.
See related editorial on page 1209.
Supported by research grants from the Kentucky Department of Health and Human Services and the Telford Foundation.
Portions of the Materials and Methods section have been published previously in van Nagell JR Jr, DePriest PD, Ueland FR, DeSimone CP, Cooper AL, McDonald JM, et al. Ovarian cancer screening with annual transvaginal sonography: findings of 25,000 women screened. Cancer 2007;109:1887–96. © 2007 American Cancer Society.
Corresponding author: John Rensselaer van Nagell Jr, MD, Division of Gynecologic Oncology, University of Kentucky-Markey Cancer Center, 800 Rose Street, Lexington, KY 40536-0293; e-mail: Jrvann2@email.uky.edu.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To estimate the effect of ultrasonographic screening on stage at detection and long-term disease-specific survival of women with epithelial ovarian cancer.
METHODS: Eligibility included all asymptomatic women aged 50 years and older and women aged 25 years and older with a documented family history of ovarian cancer. From 1987 to 2011, 37,293 women received annual ultrasonographic screening. Women with abnormal screens underwent tumor morphology indexing, serum biomarker analysis, and surgery.
RESULTS: Forty-seven invasive epithelial ovarian cancers and 15 epithelial ovarian tumors of low malignant potential were detected. No women with low malignant potential tumors experienced recurrent disease. Stage distribution for invasive epithelial cancers was: stage I, 22 (47%); stage II, 11 (23%); stage III, 14 (30%), and stage IV, 0 (0%). Follow-up varied from 2 months to 20.1 years (mean, 5.8 years). The 5-year survival rate for invasive epithelial ovarian cancers detected by screening was: stage I, 95%±4.8%; stage II, 77.1%±14.5%; and stage III, 76.2%±12.1%. The 5-year survival rate for all women with invasive epithelial ovarian cancer detected by screening as well as interval cancers was 74.8%±6.6% compared with 53.7%±2.3% for unscreened women with ovarian cancer from the same institution treated by the same surgical and chemotherapeutic protocols (P<.001).
CONCLUSION: Annual ultrasonographic screening of asymptomatic women achieved increased detection of early-stage ovarian cancer cases and an increase in 5-year disease-specific survival rate for women with ovarian cancer.
LEVEL OF EVIDENCE: II
Ovarian cancer remains the leading cause of gynecologic cancer mortality in the United States despite advances in radical surgery, postoperative care, and chemotherapy.1 In 2010, more than 15,000 deaths from ovarian cancer were reported in the United States alone.1 Although certain symptoms have been associated with ovarian cancer,2,3 these symptoms are nonspecific, and the majority of women continue to present with advanced-stage disease. Early-stage ovarian cancer, however, is highly curable when treated by conventional therapy.4 Screening asymptomatic women at risk for ovarian cancer has been proposed as a means to facilitate earlier diagnosis and improve survival.
In 1987, the University of Kentucky Ovarian Cancer Screening Trial was initiated to assess the efficacy of annual transvaginal ultrasonography as a screening method for ovarian cancer.5 Since that time, free screening has been provided to more than 37,000 women. The following investigation was performed to document stage at detection and long-term survival of patients with ovarian cancer detected by screening in this trial.
MATERIALS AND METHODS
Portions of the “Materials and Methods” have been published previously6 and are repeated here. Women who enrolled in the University of Kentucky Ovarian Cancer Screening Trial from January 1987 to June 2011 were evaluated. This trial was approved by the University of Kentucky Human Investigation 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 was obtained, each patient underwent screening according to the algorithm illustrated in Figure 1. Since 2000, transvaginal ultrasonography has been performed using General Electric Logiq 400 units with a 5-mHz vaginal probe as described previously.6 Doppler flow and three-dimensional ultrasonography were performed in women with persisting ovarian abnormalities using a General Electric Voluson 730 ProV unit with a 5- to 9-mHz vaginal probe. All ultrasonographic 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 Medlog database on a local network. Criteria for abnormality included an ovarian volume more than 20 cm3 for premenopausal women and more than 10 cm3 for postmenopausal women. These values were used because they were more than 2 standard deviations above the mean volume of normal ovaries in premenopausal and postmenopausal women.7 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 repeat ultrasonogram 4–6 weeks later. Women who had abnormal second screens had a serum CA 125 determination, tumor morphology indexing, and Doppler flow ultrasonography. Morphology indexing was performed according to the classification of Ueland and colleagues.8 Each tumor was given a score from 1 to 10 according to increasing morphologic complexity and volume (Fig. 2). During the last 5 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 have been followed without surgery by repeat ultrasonography at 6-month intervals. 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 surgical removal of the tumor. During the past 15 years of this investigation, every effort was made to perform laparoscopic tumor removal as the initial step in the operative evaluation of women with persisting ovarian tumors detected by screening.
At the time of laparoscopy, ovarian tumors were placed in an endoscopic bag intra-abdominally and removed through a midline subumbilical incision. Patients with ovarian cancer on frozen section or patients with obvious metastatic disease at laparoscopy underwent immediate exploratory laparotomy and staging. Tumors were classified histologically according to the World Health Organization system and were staged according to the International Federation of Gynecology and Obstetrics system. After surgery, patients were treated according to the cell type, histologic differentiation, and stage of each tumor, usually with six cycles of combination platinum-based 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. Cause of death was confirmed by analysis of relevant clinical records and state death certificates.
Patients with epithelial ovarian cancer entered in the University of Kentucky Tumor Registry or the statewide Kentucky Cancer Registry from 1995 to 2011, but who did not receive screening, served as control groups for this investigation. These women were from the same geographic area as women in the screening group and were referred to the University of Kentucky-Markey Cancer Center or other institutions served by the Kentucky Cancer Registry after clinical detection. The time period for evaluation of the control groups was chosen because after 1995, all patients were surgically staged and received platinum and taxane chemotherapy. Women in the control group were not matched case-by-case to women in the screening group but represented disease-specific survival rates of local and regional patients with ovarian cancer detected without screening. Control patients treated at the University of Kentucky-Markey Cancer Center all underwent surgical staging and maximum tumor cytoreduction and received at least six courses of combination carboplatin and taxane chemotherapy at this institution.
Proportions were compared by using χ2 statistics. Statistical significance was determined at the .05 level. Survival rate 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. Life table plots are shown in place of stepwise Kaplan-Meier plots because screened patients had longer survival times than unscreened members of the comparison groups.
Thirty-seven thousand two hundred ninety-three women enrolled in the University of Kentucky Ovarian Cancer Screening Trial from January 1987 to June 2011. A positive family history of ovarian cancer was documented in 8,309 (22%) of these women. Clinical characteristics of the women screened are illustrated in Table 1. Women enrolled in this study underwent a total of 205,190 scans (mean, 5.5 scans per participant). One or both ovaries were visualized in 169,197 scans (87.6%). Ultrasonographically undetectable ovaries were considered normal for purposes of this investigation.
Table 1-a. Clinical ...Image Tools
Five hundred twenty-three women (1.4%) with a persisting ovarian tumor on transvaginal ultrasonography underwent surgery (Table 2). The most common histologic diagnoses were: serous cystadenoma, primary ovarian carcinoma, endometrioma, and mucinous cystadenoma. Fifteen epithelial tumors of low malignant potential, five nonepithelial ovarian malignances, and nine cancers metastatic to the ovary were detected by screening.
The statistical definitions used in this investigation are presented in Table 3. The 76 women with an abnormal screen and invasive epithelial ovarian cancer (n=47), ovarian tumors of low malignant potential (n=15), nonepithelial ovarian cancer (n=5), or cancer metastatic to the ovary (n=9) were considered true-positives. The 447 women with positive screens who had benign ovarian tumors were considered false-positives. The 36,758 patients with negative screens who did not have ovarian cancer were classified as true-negatives. The 12 women who developed ovarian cancer within 1 year of a negative scan were considered false-negatives. Using these data, the sensitivity of transvaginal ultrasonography screening was 86.4%, and the specificity was 98.8%. The positive predictive value of an abnormal screen was 14.53%, and the negative predictive value of a normal screen was 99.97%. After 2006, the positive predictive value increased to 20.17% when the screening algorithm was changed such that surgery was not recommended in women with unilocular cystic ovarian tumors or septated cystic ovarian tumors less than 10 cm in diameter.
Forty-seven women with invasive epithelial ovarian cancer and 15 women with epithelial ovarian tumors of low malignant potential detected by screening are the subjects of the present investigation. The five women with nonepithelial ovarian cancer and the nine women with cancer metastatic to the ovary are not considered further in this study.
Demographic and histologic variables in women with low malignant potential epithelial ovarian tumors are as follows: the mean age of these women was 61.7 years (median, 63 years; range, 48–78 years), the mean weight was 167 pounds (median, 162 pounds; range, 100–240 pounds), and the mean gravidity was 2.0 (median, 2; range, 0–6). Thirteen of these tumors contained both cystic and solid components on ultrasonography, and two were entirely solid. The mean morphology index score was 5.1 (median, 5; range, 3–7) compared with 3.5 (median, 3; range, 0–10) for patients with benign tumors (P<.001). Forty percent of women with low malignant potential ovarian tumors had a palpable abnormality on clinical examination, and only two had an elevated serum CA 125 (more than 35 units/mL). Twenty percent of women with a low malignant potential tumor (3 of 15) reported a family history of ovarian cancer, and only one was diagnosed under the age of 50 years. The stage distribution of women with low malignant potential ovarian tumors was as follows: stage IA, six; stage IB, two; stage IC, six; and stage IIIA, one. Twelve patients had serous ovarian tumors, one patient had an endometrioid ovarian tumor, and two patients had a mucinous ovarian tumor, all of borderline malignancy. An ovarian abnormality was detected on the first screen in 53.3% of these cases. All women were treated primarily by surgery, and none received postoperative chemotherapy. Patients have been followed 0.2–14.8 years (mean, 6.2 years; median, 6 years) after diagnosis, and none has developed tumor recurrence or died of any cause.
Demographic and histologic variables in the 47 women with invasive epithelial ovarian cancer detected by screening are as follows: the mean age of these women was 64.5 years (median, 66 years; range, 36–86 years), the mean weight was 158 pounds (median, 151 pounds; range, 98–270 pounds), and the mean gravidity was 2.3 (median, 2; range, 0–8). An abnormality in ovarian morphology or volume was detected on the first screen in 16 patients (34%) and on subsequent screens in 31 patients (66%). All ovarian malignancies were solid or complex (both solid and cystic components) except one with cystic morphology and a thickened cyst wall. The mean morphology index score of ovarian malignancies was 6.1 (median, 6; range, 1–10) compared with 3.5 (median, 3; range, 0–10) for benign ovarian tumors and significantly different (P<.001). Twenty-one of these women (45%) had a palpable abnormality on clinical examination (note that a physical examination was performed only on patients in which the ultrasonographic examination was abnormal and was biased by knowledge of the ultrasound result.) Thirteen percent of women with invasive ovarian cancer detected by screening (six of 47) reported a family history of ovarian cancer with two women diagnosed under the age of 50 years. At the time of surgery, 22 of the 47 women (47%) with epithelial ovarian cancer detected by screening had stage I disease and 11 (23%) had stage II disease. In contrast, 701 of 2,560 (27%) unscreened women with clinically detected epithelial ovarian cancer treated at hospitals throughout Kentucky and entered into the Kentucky Tumor Registry had stage I or stage II disease at the time of diagnosis (P<.01). Fourteen women (30%) in the screening group had stage III ovarian cancer at the time of detection as compared with 46% in the unscreened group (P=.028). There was also a substage shift within stage III ovarian cancer in the screening group. Half of the women with stage III ovarian cancers detected by screening had stage IIIA or stage IIIB tumors, whereas 84% of unscreened women with stage III ovarian cancer presented with stage IIIC disease (P<.01). There were no cases of stage IV ovarian cancer detected in women undergoing screening either at the initial prevalence screen or in subsequent incidence screens.
Serum CA 125 was elevated (more than 35 units/mL) in 10 of 31 women (32%) with stage I or stage II ovarian cancer detected by screening and in 11 of 14 women (79%) with stage III disease (note that two women did not have a preoperative CA 125 determination). The cell types of the ovarian cancer were as follows: serous carcinoma, 18; adenocarcinoma, 14; endometrioid carcinoma, 12; clear cell carcinoma, two; and mucinous carcinoma, one. Four tumors were well differentiated, nine were moderately differentiated, and 34 were poorly differentiated. According to the histologic criteria of Kurman and Shih,9 10 women (21%) had type I ovarian cancer and 37 women (79%) had type II ovarian cancer.
Patients with invasive ovarian cancer all underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, maximal tumor cytoreduction, and staging. Complete tumor debulking (no visible residual disease) was achieved in all patients with stage I–IIIA disease. Eighty-six percent of patients with stages IIIB and IIIC disease were cytoreduced to less than 1 cm residual disease. Three patients with stage IA grade 1 endometrioid carcinoma were treated by surgery alone. The remaining patients all received a minimum of six cycles of platinum and taxane chemotherapy. For the past 10 years of this investigation, patients requiring chemotherapy usually have received six cycles of intravenous carboplatin and paclitaxel every 3 weeks as their initial postsurgery treatment regimen.
After therapy, patients were followed from 0.1 to 20.1 years (mean, 5.8 years; median, 5 years) and none have been lost to follow-up. To date, nine screen-detected women have died of ovarian cancer, and six screen-detected women have died of other causes with no evidence of disease. Thirty-one patients are alive with no evidence of disease, and one patient is alive with disease. The causes of death in patients who died with no evidence of ovarian cancer are as follows: two patients died of a myocardial infarction and one each of multiple myeloma, chronic obstructive airway disease, and colon cancer. One of 22 patients (4.5%) with stage I disease, four of 11 patients (36%) with stage II disease, and four of 14 (29%) with stage III disease have died of ovarian cancer. The 5-year survival rate for invasive epithelial ovarian cancers detected by screening was: stage I, 95%±4.8%; stage II, 77.1%±14.5%; and stage III, 76.2%±12.1%. During this trial, 12 women have developed interval ovarian cancer within 1 year of a normal screen (false-negative), and seven of them have died of disease. These women generally had poorly differentiated cancers with minimal ovarian enlargement on transvaginal ultrasonography, which were diagnosed 6–12 months after a normal scan. The 2-year and 5-year survival rates for these interval cases were 75%±12.5% and 57%±14.6%, respectively.
The 5-year disease-free survival rate for women with stage I and stage II epithelial ovarian cancer detected by screening was 95%±4.8% and 77.1%±14.5%, respectively. The survival rates for women with stage I or stage II ovarian cancer did not vary significantly in the screening or control groups (Fig. 3). However, the survival rate for women with advanced disease was significantly higher in the screening group (Fig. 3). This is attributable to the fact that there were proportionally more cases of stage IIIA and IIIB ovarian cancers detected by screening and that no patient developed stage IV disease while being screened. The 5-year disease-free survival rate for the entire group of women whose invasive epithelial ovarian cancers were detected by screening was 84.6%±5.6% as compared with 53.7%±2.3% in unscreened women with epithelial ovarian cancer treated at the University of Kentucky-Markey Cancer Center from 1995 to 2011 (P<.001). The women in the control group all were surgically staged and treated by the same surgical and chemotherapeutic protocols as those women whose cancers were detected by screening. The 5-year survival rate for women in the screened group was also significantly higher (P<.001) than that of unscreened women treated at multiple centers throughout the state and entered from 1995 to 2011 in the Kentucky Cancer Registry (84.6%±5.6% compared with 48.4%±1.2%). When the interval (false-negative) cases are included, the 5-year disease-free survival rate for women with ovarian cancer in the screening group is 74.8%±6.6%, which remains significantly (P<.001) higher than those women treated at this institution who did not have screening (53.7%±2.3%).
Theoretically, the use of screening to detect ovarian cancer at an earlier stage should result in more curable cases; however, there are limited data to suggest that screening actually results in reduced ovarian cancer mortality.10–15 Screening research involves analysis of large numbers of women and takes considerable planning, discipline, time, and financial support to perform. Ovarian cancer meets the criteria of a disease that should benefit from screening.16 First, ovarian cancer is highly curable with conventional treatment methods when detected at an early stage. Numerous studies have confirmed that the 5-year survival rate for women with stage I epithelial ovarian cancer is as high as 95% in major cancer centers.4 Recent studies have indicated that symptoms such as early satiety, abdominal bloating, and pelvic pain occur more commonly in women with ovarian cancer than in control patients without the disease.2,3 However, these symptoms are nonspecific and are often ignored by many women, resulting in significant delays before seeking medical evaluation. It is estimated that without screening, only 15% of ovarian cancers are localized to the ovary at the time of diagnosis.4 This is understandable because ovaries are palpable in less than 30% of postmenopausal women at the time of examination under anesthesia.17 Therefore, it is extremely difficult to detect subtle changes in ovarian morphology or volume associated with early-stage ovarian cancer by clinical examination alone.
One of the difficulties in designing screening strategies for ovarian cancer is that it is not a common disease. The incidence of ovarian cancer in the general population is 20–30 per 100,000 in women younger than 40 years of age and rises to 40 per 100,000 at the age of 50 years.18–20 Therefore, screening studies must focus specifically on women who are at high risk for the disease. Entry criteria for the present screening trial included only asymptomatic women older than age 50 years or women older than age 25 years with a documented family history of ovarian cancer. The screening algorithm followed in this investigation used transvaginal ultrasonography as the initial screening test with serum CA 125 obtained only in women with a persisting ultrasonographic abnormality. This algorithm detected 47 invasive epithelial ovarian cancers and 15 epithelial ovarian tumors of low malignant potential in 37,293 women screened or 1.6 epithelial ovarian cancer cases detected per 1,000 women screened.
An important factor in screening is the interval between the onset of ovarian cancer and the presence of clinical symptoms (the preclinical phase) during which screening intervention should lead to earlier detection. Recently, Crum and coworkers21 and Kurman and Shih9 have postulated that there are two types of epithelial ovarian cancer. Type I ovarian cancers are typically low grade endometrioid, clear cell, or mucinous cell types and have profiles of gene expression similar to those of low malignant potential tumors. In contrast, type II ovarian cancers are high-grade serous carcinomas, endometrioid carcinomas, or undifferentiated carcinomas, which are biologically aggressive. Type II ovarian cancers typically display p53 mutations and are thought to have a shorter preclinical phase than type I tumors. According to this model, annual screening would be expected to be most effective in detecting type I tumors while missing the more aggressive type II tumors, which are responsible for the majority of ovarian cancer deaths. In the present investigation, 21 of the 33 women (64%) with stage I or II invasive epithelial ovarian cancers detected by screening had poorly differentiated serous carcinomas, poorly differentiated endometrioid carcinomas, or undifferentiated adenocarcinomas (type II cancers). Sixteen of these 21 women (76%) are alive and well with no evidence of disease after conventional treatment with surgery and platinum-based chemotherapy. One can postulate that without screening, the majority of these women would have progressed rapidly to advanced-stage ovarian cancer, and many would have died of disease.
A concern about ultrasonographic screening is a low positive predictive value in differentiating malignant from benign ovarian tumors. In the multicenter Prostate, Lung, Colorectal, and Ovarian Cancer trial, for example, 19.5 surgeries were required to detect one ovarian cancer (positive predictive value 5.1%) when screening was performed using a combination of transvaginal ultrasonography and serum CA 125.13 In the present investigation, 523 women with persisting ovarian tumors underwent surgery. Forty-seven of these women had invasive epithelial ovarian cancer, 15 had epithelial ovarian tumors of borderline malignancy, five had nonepithelial ovarian cancer, and nine had cancer metastatic to the ovary. Therefore, 6.9 surgical procedures were performed per ovarian cancer detected (positive predictive value 14.53%). The difference in positive predictive value noted in this trial and that reported in the Prostate, Lung, Colorectal, and Ovarian Cancer trial can be explained partially by a higher cancer prevalence in the screened population and by two modifications in the University of Kentucky screening algorithm, which were adopted in the past 5 years. First, analysis of more than 3,200 unilocular cystic ovarian tumors less than 10 cm in diameter detected by screening revealed that the risk of malignancy in these tumors was essentially nonexistent. Women with these tumors were followed ultrasonographically for an average of 6.3 years, and none developed ovarian cancer.22 As a result, the screening algorithm was changed, and cystic ovarian tumors less than 10 cm in diameter were no longer removed surgically. In a subsequent investigation,23 2,870 complex septated cystic ovarian tumors identified by ultrasonographic screening were evaluated for risk of malignancy. Surgery was performed in 128 women and no tumor with this morphologic pattern was malignant. The remaining women were followed ultrasonographically every 4–6 months without surgery for an average of 6.4 years. Thirty-eight percent of these tumors resolved spontaneously, and no patient developed ovarian cancer. Therefore, the screening algorithm was further amended in 2009 such that surgery was not recommended in women with septated cystic ovarian tumors without solid areas or papillary projections. Ovarian tumors with these two morphologic patterns made up 55% of the total abnormalities detected by screening. As a result of these changes, the positive predictive value of screening in this trial increased from 14.1% (1987–2006) to 20.2% (2006–2011). Finally, a specific treatment algorithm was followed in this trial for women with a persisting ovarian abnormality on transvaginal ultrasonography. This included careful morphologic evaluation of each tumor, Doppler analysis of tumor blood flow, and serum biomarker analysis before a patient underwent surgery. In the Prostate, Lung, Colorectal, and Ovarian Cancer trial, there was no uniform treatment algorithm, and treatment was at the discretion of the patient's primary care physician.14 Clearly, further research is needed concerning the relationship of tumor morphology, molecular genetic patterns, and biomarker profiles to risk of malignancy so that surgery can be avoided in women with ovarian tumors at minimal risk for neoplasia. This should result in progressively increasing the positive predictive value for multimodality screening.
One of the objective measurements of an effective screening test is its ability to lower stage at detection and disease-specific mortality. In the Prostate, Lung, Colorectal, and Ovarian Cancer trial, both transvaginal ultrasonography and CA 125 were evaluated as screening tests. Although transvaginal ultrasonography was associated with a low positive predictive value, 72% of cases detected by ultrasonography alone were stage I or stage II.13 Screening with serum CA 125 was associated with a higher positive predictive value, but 74% of biomarker-detected ovarian cancers were stage IIIC or IV. Data from the present trial are consistent with these findings in that 33 of the 47 cases (70%) of the women whose ovarian cancers were detected by transvaginal ultrasonography screening had stage I or II disease as opposed to 27% of women with clinically detected ovarian cancer from the same population referred to institutions throughout the state (P<.01). Similarly, in the multi-institutional U.K. Collaborative Trial of Ovarian Cancer Screening trial, 48% of ovarian cancers detected in the prevalence screen by multimodal screening had stage I–II disease compared with 26% in the unscreened population.24
The increase in long-term ovarian cancer survival observed in the screening group in the present trial is directly attributable to lower stage at detection. The 5-year survival rate for women with stage I or II epithelial ovarian cancer was 89%, and 70% of the total screening group had these two stages of disease at the time of detection. Whereas more than two thirds of women in the screening group were detected with stage I–II disease, more than two thirds of unscreened women with clinically detected ovarian cancer presented with stage III–IV ovarian cancer. There was also a substage shift within stage III in the screening group with 50% of women being detected with stage IIIA or IIIB disease as opposed to only 16% in women without screening. Finally, no woman in the screening group had or developed stage IV ovarian cancer during this trial, whereas 19.6% of unscreened women with ovarian cancer had stage IV disease at the time of clinical diagnosis.
Data from the present investigation indicate that annual ultrasonographic screening of women at risk for ovarian cancer caused a decrease in stage at detection and site-specific ovarian cancer mortality when compared with women from the same geographic area who did not have screening. The observed 14.5% positive predictive value associated with transvaginal ultrasonography screening is unacceptably low, and routine screening of the general population cannot be recommended at the present time. However, focused research concerning risk of malignancy in ultrasonographically identified ovarian tumors should result in more selective surgery and an increase in positive predictive value to levels associated with screening for other malignancies.
The importance of early detection in ovarian cancer is evident in that more than two thirds of asymptomatic women with ovarian cancer detected by screening in the present trial had localized disease at the time of detection, and their 5-year survival rate was nearly 90%. In the absence of early detection, most women will continue to present with advanced-stage disease for which the cost of treatment is high and the cure rate is low.
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