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Keywords:

  • gynecologic malignancies;
  • laparoscopy;
  • morphology index;
  • ovarian volume;
  • predictive value;
  • screening frequency

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Ovarian cancer has the highest mortality rate of all gynecologic malignancies, and most women present with advanced-stage disease. The current investigation was performed to determine the efficacy of annual transvaginal sonography (TVS) as a screening method for ovarian cancer.

METHODS

Annual TVS screening was performed on 25,327 women from 1987 to 2005. Asymptomatic women aged ≥50 years and women aged ≥25 years who had a family history of ovarian cancer were eligible for participation in this trial.

RESULTS

Among 364 patients (1.4%) with a persisting ovarian tumor on TVS who underwent exploratory laparoscopy or laparotomy with tumor removal, 35 primary invasive ovarian cancers, 9 serous ovarian tumors of low malignant potential, and 7 cancers metastatic to the ovary were detected. Stage distribution was as follows: 28 patients had stage I disease, 8 patients had stage II disease, and 8 patients had stage III disease. Four patients died of disease, 2 patients died of other causes, and 38 patients were alive and well from 0.5 years to 15.8 years after diagnosis (mean, 5.3 years). Nine women developed ovarian cancer within 12 months of a negative screen (false-negative results), and 3 of these patients died of disease. TVS screening had a sensitivity of 85.0%, specificity of 98.7%, positive predictive value of 14.01%, and negative predictive value of 99.9%. After 107,276 screening years, there have been 7 ovarian cancer deaths in the annually screened population and 3 ovarian cancer deaths among women who were noncompliant. Excluding patients with nonepithelial or borderline ovarian malignancies, the survival of patients with ovarian cancer in the annually screened population was 89.9% ± 10.1% at 2 years and 77.2% ± 22.8% at 5 years.

CONCLUSIONS

TVS screening, when it was performed annually, was associated with a decrease in disease stage at detection and with case-specific ovarian cancer mortality, but it was not effective in detecting ovarian cancers in women who had normal ovarian volume. Cancer 2007; © 2007 American Cancer Society.

Despite advances in radical surgery, postoperative care, and chemotherapy, ovarian cancer remains the fourth leading cause of cancer mortality among women in the United States.1 This year, over 16,000 deaths from ovarian cancer will be reported in the United States alone. Early-stage ovarian cancer produces few specific symptoms, and pelvic examination is notably inaccurate in detecting subtle changes in ovarian size and morphology, particularly in postmenopausal women.2 Consequently, most patients continue to present with advanced-stage disease, for which the prognosis is poor. Early-stage ovarian cancer, however, is highly curable when it is treated by conventional therapy.3, 4 Therefore, screening asymptomatic, high-risk women has been proposed as a means to detect ovarian cancer at an earlier and more curable stage.5–13

In 1987, the University of Kentucky Ovarian Cancer Screening Project was initiated to assess the efficacy of annual transvaginal sonography (TVS) as a screening method for ovarian cancer. Since then, free screening has been provided to >25,000 women. The screening algorithm used has remained the same, except that, now, women with persisting, unilocular, cystic ovarian tumors that measure <5 cm in greatest dimension are followed at 6-month intervals with ultrasound instead of undergoing laparoscopic tumor removal. The current report summarizes the data from the trial.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients

Patients who enrolled in the University of Kentucky Ovarian Cancer Screening Project from January 1987 to May 2005 were evaluated. Eligibility criteria included 1) all asymptomatic women aged ≥50 years and 2) asymptomatic women aged ≥25 years with a documented family history of ovarian cancer in at least 1 primary or secondary relative. Genetic testing was not performed routinely as part of this trial. All study participants completed a questionnaire that included past medical history, surgical history, menopausal status, hormonal use, and family history of cancer. Menopause was defined as the absence of menses for 12 months. Any woman with a known ovarian tumor or a personal history of ovarian cancer was excluded from this investigation.

After informed consent was obtained, each patient underwent screening according to the algorithm illustrated in Figure 1. TVS was performed initially with Aloka 620 and Aloka 680 ultrasound units (Aloka, Tokyo, Japan)with a 5-mHz vaginal probe, as described previously.12 Since 2000, TVS has been performed using General Electric (Milwaukee, Wis) Logiq 400 units with a 5-mHz vaginal probe. Doppler flow and 3-dimensional sonography were performed in selected patients using a General Electric Voluson 730 ProV unit with a 5- to 9-mHz vaginal probe. All sonographic images were reviewed by at least 1 of the authors. At each screen, both ovaries were measured in 3 dimensions. Ovarian volume was calculated by 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 >20 cm3 for premenopausal women and >10 cm3 for postmenopausal women. These values were used because they were >2 standard deviations (SD) above the mean volume of normal ovaries in premenopausal and postmenopausal women.14 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 sonogram in 4 to 6 weeks. Women who had an abnormal second screen had a serum CA-125 determination, tumor morphology indexing, Doppler flow sonography, and (more recently) serum proteomic analysis. Morphology indexing was performed according to the classification of Ueland and colleagues.15 Each tumor was given a score from 1 to 10 according to increasing morphologic complexity and volume (Fig. 2). Women who had unilocular cystic ovarian tumors that measured ≤5 cm in greatest dimension and a normal serum CA-125 were followed with repeat sonography at 6-month intervals. Women who had persisting, complex ovarian tumors or women who had a cystic ovarian tumor and an elevated serum CA-125 level were advised to undergo surgical removal of the tumor. During the past 10 years of this trial, every effort was made to perform laparoscopic tumor removal as the initial step in the operative evaluation of patients with persisting ovarian tumors detected at screening.

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Figure 1. Study algorithm.

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Figure 2. Morphology index.

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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 (WHO) system and were staged according to the International Federation of Gynecology and Obstetrics (FIGO) system. After surgery, patients were treated according to the cell type, histologic differentiation, and stage of each tumor, usually with a 6-month course of combination chemotherapy. Patients with ovarian cancer were followed at monthly intervals during treatment, every 3 months for 2 years, and every 6 months thereafter. Follow-up data on all patients were coordinated with the American Cancer Society and the Kentucky State Department of Vital Statistics. Three hundred eighty patients with ovarian cancer who were entered into the University of Kentucky Tumor Registry from 1987 to 2005 and who did not receive screening served as a historic control group for this investigation.

Statistical Methods

Proportions were compared by using chi-square statistics or Fisher exact tests. Means were compared by using 2-sample t statistics. Statistical significance was determined at the .05 level. Patient survival was estimated using the Kaplan-Meier method.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

There were 25,327 women who enrolled in the study from January 1987 to May 2005, and a family history of ovarian cancer was documented in 5868 of those women (23.2%). The clinical characteristics of the patients screened are illustrated in Table 1. The mean age of these patients was 56 years (SD, 10.5 years; range, 25–92 years). The mean height was 162.56 cm (SD, 6.6 cm; range, 127–195.58 cm), and the mean weight was 72.21 kg (SD, 15.9 kg; range, 36–166.9 kg). The mean parity was 2.4 (SD, 1.4; range, 0–17), and 3705 women (14.6%) were nulliparous. Women enrolled in the study underwent a total of 120,569 scans (mean, 4.8 scans per participant). One or both ovaries were visualized in 101,299 scans (84%). Sonographically undetectable ovaries were considered normal for the purposes of this investigation.

Table 1. Clinical Characteristics of Patients Screened (n = 25,327)
VariableMeanRangeNo. of patients (%)
Age, y5625–92 
Parity2.40–17 
Weight, kg71.2136–166.9 
Height, cm162.56127–195.58 
Family history
 Ovarian cancer  5868 (23.2)
 Breast cancer  9396 (37.1)
 Colon cancer  6066 (24)
History of hormone replacement  8021 (31.7)
Hormone replacement on last visit  5397 (21.3)
Nulliparous  3705 (14.6)

Three hundred sixty-four women (1.4%) with a persisting ovarian tumor on TVS underwent surgery. Histologic diagnoses of the 364 ovarian tumors removed are presented in Table 2. The most common diagnosis was ovarian serous cystadenoma followed by primary ovarian cancer and endometrioma. Forty-four women had primary ovarian cancer, including 39 epithelial neoplasms and 5 ovarian stromal neoplasms. Patients who had a positive family history of ovarian cancer did not have a statistically higher frequency of ovarian carcinoma or benign ovarian tumors than patients without this history. All ovarian malignancies except 1 had solid components or papillary projections from the tumor wall. One ovarian carcinoma was predominantly cystic, but it had an abnormally thickened wall. Morphology index (MI) scores of the tumors removed varied from 0 to 10. The mean MI value for benign tumors was 3.5 (SD, 2.3; range, 0–10) compared with a mean MI value of 6 (SD, 1.9; range, 3–10) for ovarian malignancies (P < .001). One hundred fifty-three tumors were unilocular without wall abnormalities, and none were malignant.

Table 2. Histologic Findings in Patients With Persistently Abnormal Screens (n = 364)
FindingNo. of patients
Primary ovarian cancer44
Nonovarian cancer7
 Appendix3
 Primary peritoneum2
 Breast1
 Endometrium1
Serous cystadenoma153
Endometrioma30
Mucinous cystadenoma19
Cystic teratoma18
Fibroma/thecoma/Brenner tumor25
Leiomyoma4
Hydrosalpinx/paratubal cyst25
Other39

Clinical and pathologic findings in the 44 patients who had primary ovarian cancer detected by annual screening are presented in Table 3. Stage distribution of these patients was as follows: 28 patients had stage I disease, 7 patients had stage II disease, and 8 patients had stage III disease. Nine patients had serous ovarian tumors of borderline malignancy. Five patients with stage I ovarian cancer (18%) had a palpable abnormality on clinical examination. Nine patients with stage I invasive ovarian cancer had preoperative CA-125 determinations, and antigen levels were elevated (>35 U/mL) in 1 patient (11%). Twenty-one of 44 primary ovarian cancers (48%) were detected on the first screen, and the remaining primary ovarian cancers were detected on subsequent screens. Four of 44 patients (9%) who had primary ovarian cancers detected by annual screening have died of disease. Three of those patients had stage III ovarian cancer at the time of their first or second screen and died of disease from 1.8 years to 7.1 years after diagnosis. One patient (No. 32) had a poorly differentiated stage IIA ovarian serous cystadenocarcinoma detected on the 12th screen and died of disease 1.3 years after she underwent surgical debulking and received carboplatin/taxol chemotherapy. Thirty-eight patients remain alive and well with no evidence of disease from 0.5 years to 15.8 years (mean, 5.3 years) after diagnosis, and 2patients without evidence of disease died of other causes 3.1 years and 8.0 years after diagnosis.

Table 3. Clinicopathologic Findings in Patients With Primary Ovarian Cancer Detected by Screening (n = 44)
PatientAge at Dx, yFamily historyNo. of screensPhysical examinationTVS findingTVS volume, cm3TVS MICA-125, U/mLHistologyTumor stageTreatmentStatusFollow-up, y
  1. Dx indicates diagnosis; TVS, transvaginal sonography; MI, morphology index; S, surgery; C, chemotherapy; NED, no evidence of disease; DOC, dead from other causes; DOD, dead of disease.

172Yes3NormalComplex mass19857Granulosa cell tumor grade 2IAS and CNED15.8
250No1NormalComplex mass19814Adenocarcinoma grade 3IAS and CNED15.2
342Yes2PalpableCystic mass27314Serous cystadenocarcinoma grade 3IAS and CNED12.3
436No1NormalComplex mass325Endometrioid carcinoma grade 1IASNED12.3
555Yes1NormalComplex mass156Granulosa cell tumor grade 2IAS and CNED11.5
658No5PalpableComplex mass946Serous ovarian tumor of borderline malignancyIASNED9.9
766No1NormalComplex mass40637Endometrioid carcinoma grade 2IAS and CNED9.9
864Yes1NormalComplex mass253Endometrioid carcinoma grade 2IAS and CNED9.5
963No1NormalComplex mass223812Serous ovarian tumor of borderline malignancyIASNED8.3
1065No6NormalComplex mass366925Endometrioid adenocarcinoma grade 2IAS and CNED5.7
1163No1NormalComplex mass1645Adenocarcinoma grade 1IASNED, DOC3.1
1257No3NormalComplex mass3310Granulosa cell tumor grade 3IASNED6.1
1369No10NormalComplex mass355Adenocarcinoma grade 3IAS and CNED4.4
1460No1NormalComplex mass51614Adenocarcinoma grade 3IASNED1.6
1558Yes7NormalComplex mass20513Granulosa cell tumor grade 2IASNED1.4
1659No1NormalSolid mass11875Ovarian tumor of borderline malignancyIASNED0.6
1771No8PalpableSolid mass163713Endometrioid carcinoma grade 2IAS and CNED0.5
1860No1NormalComplex mass91523Endometrioid adenocarcinoma grade 2IBS and CNED4.7
1953No3NormalComplex mass10374Clear cell adenocarcinoma grade 3IBS and CNED2.7
2063No1NormalComplex mass33516Serous ovarian tumor of borderline malignancyIBS and CNED1.5
2171No11NormalComplex mass20647Serous ovarian tumor of borderline malignancyIBSNED0.2
2257No3NormalComplex mass2697Granulosa cell tumor grade 1ICSNED11.0
2348Yes7PalpableComplex mass12255Serous tumor of borderline malignancyICSNED7.0
2454No3PalpableComplex mass1417Endometrioid adenocarcinoma grade 3ICS and CNED3.3
2572No7NormalSolid mass32527Serous ovarian tumor of borderline malignancyICS and CNED1.1
2664No1NormalComplex mass34421Serous ovarian tumor of borderline malignancyICSNED0.6
2763No1NormalComplex mass27526Papillary serous adenocarcinoma grade 1ICS and CNED0.6
2853No2NormalComplex mass1046Serous ovarian tumor of borderline malignancyICSNED0.3
2979No12NormalComplex mass195259Endometrioid adenocarcinoma grade 3IIAS and CNED5.4
3067No1NormalComplex mass163Adenocarcinoma grade 3IIAS and CNED4.6
3170No2PalpableComplex mass90511Papillary serous carcinoma grade 2IIAS and CNED0.1
3266No12PalpableComplex mass12977Serous cystadenocarcinoma grade 3IIAS and CDOD1.3
3356No2NormalSolid mass205Adenocarcinoma grade 3IIBS and CNED1.9
3461Yes5NormalComplex mass28516Adenocarcinoma grade 3IICS and CNED, DOC8.0
 8            
3563No2NormalComplex mass23910279Adenocarcinoma grade 3IICS and CNED11.2
3662No1PalpableSolid mass326833Adenocarcinoma grade 3IICS and CNED1.1
3769No2PalpableComplex mass52249Carcinosarcoma grade 3IIIAS and CDOD1.8
3852Yes3PalpableComplex mass35 ml435Serous ovarian tumor of borderline malignancyIIIASNED3.0
3966No1NormalComplex mass154916Adenocarcinoma grade 3IIIBS and CDOD7.1
4077No1PalpableComplex mass87716Papillary serous carcinoma grade 2IIIBS and CNED1.0
4152No1PalpableSolid mass3131059Adenocarcinoma grade 3IIICS and CDOD2.4
4272No4PalpableComplex mass3849134Mucinous cystadenocarcinoma grade 3IIICS and CNED7.5
4345Yes8PalpableComplex mass33591550Adenocarcinoma grade 3IIICS and CNED4.5
4463Yes15NormalComplex mass345214Endometrioid carcinoma grade 3IIICS and CNED3.2

Nine patients developed ovarian cancer within 12 months of a negative screen (false-negative results). Three of those patients had normal sized ovaries at the time of surgical exploration 3 months, 12 months, and 12 months after a normal screen but had extraovarian metastases resulting in a diagnosis of stage IIA ovarian cancer (1 patient) and stage IIIC ovarian cancer (2 patients). Six patients had increased ovarian volumes at the time of surgery from 2 months to 11 months after a normal screen and had stage IIC ovarian cancer (1 patient), stage IIIB cancer (1 patient), and stage IIIC cancer (4 patients). Seven of those patients had poorly differentiated ovarian carcinomas, and 2 had moderately differentiated tumors. Serum CA-125 determinations were obtained in all 9 of those patients at the time of surgery and were elevated (>35 U/mL) in 8 patients. All patients were treated with a combination of surgery and chemotherapy. Five patients were alive without evidence of disease from 0.5 years to 5.5 years after diagnosis, and 3 patients died of disease from 0.7 years to 7.0 years after diagnosis. One patient who had no evidence of disease died of a myocardial infarction 9.8 years after diagnosis.

Seven women had metastatic cancer to the ovary detected by screening (Table 4). It was believed that all of those women had a primary ovarian neoplasm prior to surgical exploration. Three of these patients had primary appendiceal cancer with metastases to the ovary and underwent hemicolectomy and ovarian tumor debulking. They remain alive without evidence of disease from 1 year to 6.3 years after treatment. Two patients had primary peritoneal cancer detected by the presence of paraovarian fluid. Both of those patients had peritoneal and ovarian surface involvement by a poorly differentiated epithelial adenocarcinoma and had no evidence of ovarian stromal invasion. One patient remains alive with disease 1.7 years after diagnosis, and the other patient has no evidence of disease 3.7 years after surgery and chemotherapy. Finally, there was 1 patient with ovarian metastasis from breast carcinoma who died of disease 7.9 years after ovarian tumor removal, and 1 patient with endometrial cancer and spread to the ovary is alive and well 4.4 years after surgery. To date, there have been no cases of operative mortality in patients who underwent surgery as part of this trial.

Table 4. Clinicopathologic Findings in Patients With Metastatic Cancer to the Ovary Detected by Transvaginal Sonography (n = 7)
CaseAge at Dx, yFamily historyNo. of screensPhysical examinationTVS finding, (volume, cm3)Site of primary cancerTreatmentStatusFollow-up, y
  1. Dx indicates diagnosis; TVS, transvaginal sonography; S, surgery; C, chemotherapy; DOD, dead of disease; NED, no evidence of disease; AWD, alive with disease.

4560No8NormalOvarian tumor (18)BreastS and CDOD7.9
4656No4NormalOvarian tumor (70)AppendixS and CNED6.3
4770No10NormalParaovarian fluid (99)PeritoneumS and CNED3.7
4867No9NormalParaovarian fluid (>100)PeritoneumS and CAWD1.7
4948No6Pelvic massOvarian tumor (76)AppendixS and CNED1.9
5071No11Pelvic massOvarian tumor (100)AppendixS and CNED1
5178No3Pelvic massOvarian tumor (76)EndometriumS and CNED4.4

Four hundred fifty-six patients (1.8%) with normal screens underwent hysterectomy and bilateral salpingo-oophorectomy for a variety of indications that were unrelated to screening. Ovarian volume and morphology were normal in all of these patients at the time of surgery, and there were no cases of ovarian neoplasia. There were 3746 postmenopausal women with 6513 unilocular cystic ovarian tumors who were followed at 3- to 6-month intervals by TVS without surgery. Duration of follow-up ranged from 4 months to 16.5 years (mean, 4.6 years). Spontaneous resolution occurred in 5381 of these cysts (83%), usually within 6 months, and no patient in this group has developed ovarian cancer.

The statistical definitions used in this investigation are presented in Table 5. There were 51 patients with positive screens who had either primary ovarian cancer or cancer metastatic to the ovary (true-positive results). There were 313 patients with positive screens who had benign ovarian tumors (false-positive results). Likewise, there were 23,706 patients with negative screens, and 9 women developed ovarian cancer within 12 months of a negative scan (false-negative results). Using these data, the sensitivity of TVS screening was 85%, and the specificity was 98.7%. The positive predictive value (PPV) of an abnormal screen was 0.1401, and the negative predictive value (NPV) of a normal screen was 0.999. Screening statistics related to date of entry into the trial, family history, and menopausal status are presented in Table 6. The screening algorithm was changed on January 1, 2001, such that patients with unilocular cystic ovarian tumors measuring ≤5 cm were followed sonographically at 6-month intervals rather than undergoing surgery. The PPV of screening increased from 8.8% (1987–2000) to 27.1% (2001–2006) as a result of this change. Likewise, the PPV of screening increased from 8.8% in premenopausal patients to 15.4% in postmenopausal patients. In patients receiving TVS screening, there have been 107,276 screening years and 10 deaths from ovarian cancer. Seven of the patients who died of ovarian cancer (4 with true-positive results and 3 with false-negative results) were compliant with the screening algorithm and were screened at yearly intervals. Two of the four women in the true-positive group who died of disease had stage III ovarian cancer at the time of their initial screen. There were 3 noncompliant patients who died of ovarian cancer. These patients returned to their local physicians with symptoms of abdominal swelling after having no screening for 21 months, 51 months, and 61 months. All 3 of those patients had stage III disease at the time of their diagnosis and died of disease from 1 year to 4.6 years after diagnosis.

Table 5. Statistical Definitions in Ovarian Cancer Screening*
TermScreenFindingsNo. of study patients
  • *

    Sensitivity (TP/TP + FN) = 85.0%; specificity (TN/TN + FP) = 98.7%; positive predictive value (TP/TP + FP) = 14.0%; negative predictive value (TN/TN + FN) = 99.9%.

True positive (TP)PositiveHistology confirms ovarian cancer51
False positive (FP)PositiveBenign ovarian histology313
True negative (TN)NegativeNo evidence of disease 12 mo after negative screen24,954
False negative (FN)NegativeOvarian cancer diagnosed within 12 mo of negative screen9
Table 6. Statistical Evaluation of Screening According to Year of Trial Entry, Family History of Ovarian Cancer, and Menopausal Status
VariableTotal no. of cases1987 to 20012001 to presentNo family historyFamily historyPremenopausalPostmenopausal
  • TP indicates true positive; FP, false positive; FN, false negative; TN, true negative; Sen, sensitivity; Spec, specificity; PPV, positive predictive value; NPV. negative predictive value.

  • *

    The screening algorithm changed, so that unilocular ovarian cysts that measured ≤5 cm in greatest dimension were followed sonographically and were not removed surgically.

Total25,32716,242908519,2706057707818,249
TP512328429744
FP313238752278672241
FN9456318
TN24,95415,977897718,9955959699817,956
Sen0.850.8510.8490.8750.750.8750.846
Spec0.9870.9850.9920.9880.9860.9890.986
PPV0.1400.0880.2710.1560.0950.0880.154
NPV0.99960.99970.99940.99970.99950.99980.9996
Screening, y*107,27690,54016,73678,39728,87937,68382,811

The survival rate of patients with ovarian cancer in the annual screening group was 92.1% ± 7.9% at 2 years and 82.4% ± 17.6% at 5 years. When we excluded the 5 patients who had granulosa cell tumors and the 9 patients who had serous ovarian tumors of borderline malignancy, the survival rate was 89.9% ± 10.1% at 2 years and 77.2% ± 22.8% at 5 years. The survival rate of all patients with ovarian cancer in the study group, including those who had cancer detected by screening and those who were diagnosed >12 months after a negative screen by clinical examination, was 88.2% ± 11.8% at 2 years and 76.6% ± 23.4% at 5 years. This compares favorably with a 2-year survival rate of 70.7% ± 2.6% and a 5-year survival rate of 48.7% ± 3.5% for patients with ovarian cancer in the University of Kentucky Tumor Registry who did not receive screening (P < .001).

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Analysis of data from nearly 20 years of screening allows us to reach certain conclusions about the benefits and limitations of TVS as a screening method for ovarian cancer. First, TVS is safe, time efficient, and well accepted by patients. In over 100,000 screens, <10 women have complained that TVS is uncomfortable. A complete screening examination usually takes from 5 minutes to 10 minutes, and no medical or surgical complications from TVS have been observed. When TVS is used in high-volume settings, its cost is well within the range of other accepted screening tests, and interobserver variation is minimal.16–18 Although there is a definite learning curve for technologists performing TVS, 1 or both ovaries were visualized in 84% of women, and ovarian tumor dimensions predicted by TVS correlated closely with recorded measurements at the time of surgery.

For a screening test to be effective, it should be sensitive and specific, and it should have both a high PPV and a high NPV.19 Furthermore, periodic screening should decrease the disease stage at detection and increase disease-specific survival in the screened population.20 The major limitations of TVS as a screening method for ovarian cancer are its moderate sensitivity and relatively low PPV. Although TVS screening accurately predicted the presence of cancer involving the ovary in 51 asymptomatic women, there were 9 patients who developed ovarian cancer within 12 months of a normal scan (false-negative results). Six of those patients had minimally enlarged ovaries at the time of surgery from 3 months to 12 months (mean, 8 months) after a normal scan but had extraovarian spread. Five of these 6 ovarian cancers were poorly differentiated. TVS did not detect an abnormality in these women, because their ovarian volume was increased minimally. Whether the addition of a serum CA-125 determination to TVS as a primary test in the screening algorithm would have resulted in the earlier detection in these women cannot be answered from these data because CA-125 measurement was obtained as a secondary test only in those patients who had a persisting abnormality on TVS. However, serum CA-125 levels were elevated in 8 of those 9 patients (88%) at the time of surgery, and it is logical to assume that marker elevation would have preceded clinical detection in some of these women. Other screening trials that were designed to answer this question are in progress.7, 13 In the current investigation, serum CA-125 levels were increased (>35 U/mL) at the time of detection in 13 of 15 patients (87%) who had stage III epithelial ovarian cancer but in only 3 of 15 patients (20%) who had stage I or II disease.

A second area of concern related to TVS screening for ovarian cancer is its relatively low PPV. Whereas TVS is accurate in identifying ovarian tumors, it is less effective in differentiating benign lesions from malignant lesions. In the current investigation, 14% of persisting complex ovarian tumors were malignant. Tumor morphology21–24 and serum biomarker patterns25–28 both have been useful in predicting the risk of malignancy in sonographically confirmed ovarian tumors. In the current investigation, all but 1 of the screen-detected ovarian malignancies were either solid tumors or cystic tumors with solid areas or papillary projections from the cyst wall. There were 153 unilocular cystic ovarian tumors that measured <5 cm in greatest dimension (MI, ≤4), and all were benign. In 2001, the screening algorithm at the University of Kentucky was changed, such that unilocular cystic ovarian tumors that measured ≤5 cm in greatest dimension were followed sonographically rather than removed surgically. Since that time, the PPV of TVS screening has increased to 27.1%, which is well within the range of other accepted screening tests, such as mammography and cervical cytology.29–31 None of these patients has developed ovarian cancer, thereby confirming the safety of following small unilocular ovarian cysts sonographically and avoiding surgery in these women. It is our current policy to follow all patients with unilocular cystic ovarian tumors that measure ≤5 cm in greatest dimension at 6-month intervals with TVS rather than proceeding with operative intervention.

The use of a single biomarker value to distinguish benign ovarian tumors from early-stage ovarian cancer has been problematic. In the current investigation, for example, serum CA-125 measurements were obtained at the time of surgery in 9 patients with stage I invasive epithelial ovarian cancer detected by screening and was elevated (>35 U/mL) in only 1 patient. Recent data suggest that serial marker determinations may be more effective than a single threshold value in identifying ovarian malignancies. Generally, serum CA-125 values rise over time in patients with ovarian cancer, whereas they remain stable or decrease in patients with benign ovarian tumors. Using a risk calculation based on progressively rising serum CA-125 levels, Skates and colleagues32 were able to increase the sensitivity of ovarian cancer detection from 62% to 86%. Therefore, serum CA-125 determinations at 2- to 4-week intervals can be helpful in establishing the risk of malignancy in a specific ovarian tumor.

Despite the aforementioned limitations, annual TVS screening decreases disease stage at detection and increases case-specific ovarian cancer survival. In the current trial, 82% of women who had ovarian cancer detected by screening had stage I or stage II disease versus 34% of women in the unscreened historic control group (P < .0001). In 107,276 screening years, 53 primary ovarian cancers were detected (44 true-positive results and 9 false-negative results). Seven deaths occurred in women who were compliant with the screening algorithm. Two of those patients had advanced-stage disease at the time of their initial screen and died of disease after treatment with surgery and chemotherapy. The survival rate for all patients with invasive epithelial ovarian cancer in the screening group was 89.9% at 2 years and 77.2% at 5 years, which was significantly higher (P < .001) than the survival rate of patients with ovarian cancer in the control group who did not have screening (2-year survival rate, 70.9%; 5-year survival rate, 48.7%).

Ovarian cancer poses specific challenges for screening. Although ovarian cancer is curable when it is detected early, it is not common, and rates of progression, even among epithelial cancers, are variable. In this trial, ovarian cancer screening was performed at yearly intervals. However, it may be necessary to increase the frequency of screening in certain high-risk women. It should be possible, as more complete molecular genetic data concerning the etiology of ovarian cancer become available, to construct more accurate risk profiles for each patient and to match screening frequency to risk of malignancy.33 Finally, investigation must continue to identify proteins or other biomarkers that are specific to ovarian cancer that can be used for early diagnosis.34, 35 This is particularly important for the detection of cancers that involve only the ovarian surface epithelium and do not produce ovarian enlargement, thus evading sonographic surveillance.

With more effective chemotherapy now available for patients with ovarian cancer, even a modest advance in the time to diagnosis should be associated with a significant survival advantage.36 In the absence of early detection, most women with ovarian cancer will continue to present with advanced-stage disease, for which the cost of treatment is high and the cure rate is extremely low. The protective effect of annual sonographic screening on ovarian cancer mortality observed in the current trial should only increase as more specific biomarkers are added to TVS in screening algorithms.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES