David Oram

Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonography.

OBJECTIVE--To assess the performance of the sequential combination of serum CA 125 measurement and ultrasonography in screening for ovarian cancer. DESIGN--The serum CA 125 concentration of each subject was determined and those with a concentration > or = 30 U/ml were recalled for abdominal ultrasonography. If ultrasonography gave abnormal results surgical investigation was arranged. Volunteers were followed up by annual postal questionnaire. SETTING--General practice, occupational health departments, ovarian cancer screening clinic. SUBJECTS--22,000 women volunteers who were postmenopausal and aged over 45 years. MAIN OUTCOME MEASURES--Apparent sensitivity, specificity, positive predictive value, years of cancer detected. RESULTS--41 women had a positive screening result and were investigated surgically. 11 had ovarian cancer (true positive result) and 30 had other disorders or no abnormality (false positive result). Of the 21,959 volunteers with a negative screening result, eight subsequently presented clinically with ovarian cancer (false negative result) and 21,951 had not developed ovarian cancer during follow up (apparent true negative result). The screening protocol achieved a specificity of 99.9%, a positive predictive value of 26.8%, and an apparent sensitivity of 78.6% and 57.9% at one year and two year follow up respectively. The estimated number of years of cancer detected by the prevalence screen was 1.4 years. CONCLUSIONS--This screening protocol is highly specific for ovarian cancer and can detect a substantial proportion of cases at a preclinical stage. Further investigation is required to determine the effect of the screening protocol on the ratio of early to late stage disease detected and on mortality from ovarian cancer.

MULTIMODAL APPROACH TO SCREENING FOR OVARIAN CANCER

1010 postmenopausal women were recruited for an ovarian cancer screening programme incorporating serum CA-125 measurement and vaginal examination as initial tests and real-time ultrasonography as a secondary procedure in selected cases. The normal range for serum CA-125 in postmenopausal women was established. The specificity for ovarian cancer of serum CA-125 measurement and vaginal examination were 97.0% and 97.3%, respectively. The combinations of serum CA-125 measurement with ultrasound and vaginal examination with ultrasound achieved specificities of 99.8% and 99.0%, respectively. 100% specificity was achieved by serum CA-125 measurement with vaginal examination and by the combination of all three tests. The findings indicate that no individual screening test has acceptable specificity for ovarian cancer in postmenopausal women. However, the combination of CA-125 measurement with ultrasound did achieve acceptable specificity and offers the most hope of a specific and sensitive method for early detection.

Prospective Study Using the Risk of Ovarian Cancer Algorithm to Screen for Ovarian Cancer

PURPOSEnTo evaluate prevalence screening in the first prospective trial of a new ovarian cancer screening (OCS) strategy (risk of ovarian cancer or ROC algorithm) on the basis of age and CA125 profile.nnnPATIENTS AND METHODSnPostmenopausal women, > or = 50 years were randomly assigned to a control group or screen group. Screening involved serum CA125, interpreted using the ROC algorithm. Participants with normal results returned to annual screening; those with intermediate results had repeat CA125 testing; and those with elevated values underwent transvaginal ultrasound (TVS). Women with abnormal or persistently equivocal TVS were referred for a gynecologic opinion.nnnRESULTSnThirteen thousand five hundred eighty-two women were recruited. Of 6,682 women randomly assigned to screening, 6,532 women underwent the first screen. After the initial CA125, 5,213 women were classified as normal risk, 91 women elevated, and 1,228 women intermediate. On repeat CA125 testing of the latter, a further 53 women were classified as elevated risk. All 144 women with elevated risk had TVS. Sixteen women underwent surgery. Eleven women had benign pathology; one woman had ovarian recurrence of breast cancer; one woman had borderline; and three women had primary invasive epithelial ovarian cancer (EOC). The specificity and positive predictive value (PPV) for primary invasive EOC were 99.8% (95% CI, 99.7 to 99.9) and 19% (95% CI, 4.1 to 45.6), respectively.nnnCONCLUSIONnAn OCS strategy using the ROC algorithm is feasible and can achieve high specificity and PPV in postmenopausal women. It is being used in the United Kingdom Collaborative Trial of Ovarian Cancer Screening and in the United States in both the Cancer Genetics Network and the Gynecology Oncology Group trials of high-risk women.

The adnexal mass: benign or malignant? Evaluation of a risk of malignancy index

Objective To validate a risk of malignancy index incorporating menopausal status, serum CA 125 level and pelvic ultrasound features in the pre‐operative diagnosis of ovarian cancer.

Risk Algorithm Using Serial Biomarker Measurements Doubles the Number of Screen-Detected Cancers Compared With a Single-Threshold Rule in the United Kingdom Collaborative Trial of Ovarian Cancer Screening

Purpose Cancer screening strategies have commonly adopted single-biomarker thresholds to identify abnormality. We investigated the impact of serial biomarker change interpreted through a risk algorithm on cancer detection rates. Patients and Methods In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 46,237 women, age 50 years or older underwent incidence screening by using the multimodal strategy (MMS) in which annual serum cancer antigen 125 (CA-125) was interpreted with the risk of ovarian cancer algorithm (ROCA). Women were triaged by the ROCA: normal risk, returned to annual screening; intermediate risk, repeat CA-125; and elevated risk, repeat CA-125 and transvaginal ultrasound. Women with persistently increased risk were clinically evaluated. All participants were followed through national cancer and/or death registries. Performance characteristics of a single-threshold rule and the ROCA were compared by using receiver operating characteristic curves. Results After 296,911 women-years of annual incidence screening, 640 women underwent surgery. Of those, 133 had primary invasive epithelial ovarian or tubal cancers (iEOCs). In all, 22 interval iEOCs occurred within 1 year of screening, of which one was detected by ROCA but was managed conservatively after clinical assessment. The sensitivity and specificity of MMS for detection of iEOCs were 85.8% (95% CI, 79.3% to 90.9%) and 99.8% (95% CI, 99.8% to 99.8%), respectively, with 4.8 surgeries per iEOC. ROCA alone detected 87.1% (135 of 155) of the iEOCs. Using fixed CA-125 cutoffs at the last annual screen of more than 35, more than 30, and more than 22 U/mL would have identified 41.3% (64 of 155), 48.4% (75 of 155), and 66.5% (103 of 155), respectively. The area under the curve for ROCA (0.915) was significantly (P = .0027) higher than that for a single-threshold rule (0.869). Conclusion Screening by using ROCA doubled the number of screen-detected iEOCs compared with a fixed cutoff. In the context of cancer screening, reliance on predefined single-threshold rules may result in biomarkers of value being discarded.

Prevention of ovarian cancer: a survey of the practice of prophylactic oophorectomy by fellows and members of the Royal College of Obstetricians and Gynaecologists

Summary. A questionnaire designed to investigate attitudes to prophylactic oophorectomy was sent to 2817 fellows and members of the Royal College of Obstetricians and Gynaecologists. A total of 1142 replies was received from those who performed regular sessions of gynaecological surgery. The number of respondents who said they would usually remove apparently normal ovaries at the time of abdominal hysterectomy from premenopausal women in age groups 35–39, 40–44, 45–49 and over 49 years was 4 (0–4%), 27 (2%), 234 (20%) and 585 (51%) respectively, and from postmenopausal women 974 (85%). The majority of respondents said that (i) they would prescribe hormone replacement therapy in oophorectomized premenopausal women (82%); (ii) they did not consider unilateral oophorectomy to have a role in prevention of ovarian cancer (84%); and (iii) they routinely discussed the question of prophylactic oophorectomy with their patients before operation (65%). Only 128 (11%) of the respondents believed that ≥10% of ovarian cancers in the UK could be prevented by prophylactic oophorectomy at the time of operation for benign disease, and 505 (44%) would perform prophylactic oophorectomy as a primary surgical procedure in women who had a strong family history of ovarian cancer.

Cytoreductive surgery in ovarian cancer.

Abstract As the overall prognosis for patients with ovarian cancer is poor, the management of this condition should be restricted to expert multi-disciplinary teams in gynaecological oncology. Apparent early stage ovarian cancer requires accurate and complete staging so that potential sites for metastases are not missed. Omitting adequate staging may have significant consequences including a negative impact on survival rates in young patients. The challenge with advanced ovarian cancer is to obtain a detailed appreciation of the extent of disease. This information allows treatment with primary chemotherapy if the cancer is considered to be inoperable and/or the general condition of the patient renders her unfit for appropriate surgery. Available data would suggest that a 5-year survival rate of 50% is only possible for those patients who have had complete cytoreduction of all tumour. Therefore, the best surgical option for patients with advanced ovarian cancer is a ‘complete’ primary surgical procedure that achieves complete clearance of the abdominal cavity rather than ‘optimal’ surgery that leaves tumour nodules up to 1u2009cm in diameter in situ in the patient.

Soluble interleukin‐2 receptor alpha is elevated in sera of patients with benign ovarian neoplasms and epithelial ovarian cancer

Background. Previous studies have established that soluble interleukin‐2 receptor alpha (sIL‐2Rα) levels are elevated in ascites and sera from individuals with advanced ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] Stage III/IV). This study was undertaken to evaluate sIL‐2Rα levels in individuals with benign ovarian neoplasms and early stage ovarian cancer (FIGO Stage I/II). Comparison with CA 125 levels was performed to assess screening potential.

The accuracy of frozen section diagnosis in apparent early ovarian cancer – results from a UK centre

Sir: There is marked variation in the use of intraoperative frozen section (FS) evaluation of adnexal malignancies in the UK. At our Centre FS is done regularly for several indications in gynaecological oncology, with significant workload implications for pathologists. We present the results of an audit of FS for suspected early ovarian cancer. The aim was to assess its accuracy and impact on patient management. We were advised by the Ethics Committee that because this study was an audit, formal National Research Ethics Service approval was not required. Accurate surgical staging is mandatory for optimal treatment of early ovarian cancer. The management options in apparent early ovarian cancer are either to stage all cases surgically, possibly unnecessarily, or to restage proven malignant cases at a second procedure. Reliable intraoperative diagnosis at the first operation enables the informed decision to proceed to full staging when indicated. Between October 2006 and May 2008 FS was considered in 71 patients with suspected early ovarian cancer. Ten cases were excluded: three because of extensive ovarian disease at laparotomy that had not been detected on preoperative imaging and seven because of non-ovarian neoplasms diagnosed through operative findings (three cases) or FS (four cases). Of the 61 cases of primary ovarian tumours, the mean age was 54 years and the majority had intermediate or high risk of malignancy index (RMI) (Table 1). Of these there were 20 (33%) malignant, 10 (16%) borderline and 31 (51%) benign tumours (Table 2). FS performed in 50 ⁄ 61 cases (82%) was found concordant with final pathology in 46 patients (92%). The overall sensitivity, specificity, positive predictive value and negative predictive value of FS for malignant and borderline ovarian tumours were 93%, 90%, 93% and 90%, respectively (Table 3). The four discrepancies were two mucinous neoplasms, one fibrothecoma with a focus of fibrosarcoma and one serous cystadenofibroma (Table 4). None of the patients in whom FS was carried out required second surgery for the ovarian tumour. It is significant that 40% of cases with borderline tumours in this study were young women keen to preserve fertility. As none was diagnosed as malignant on FS, conservative surgery was performed. The reported FS rate for ovarian lesions ranges from 4% to 47%. In our study this rate was 82%, a significant increase from 11% in comparable cases prior to the introduction in 2006 of current departmental guidelines. Decision not to perform FS shortens Table 2. Histological types of ovarian tumours

Raised serum CA 125 preceding the diagnosis of carcinoma of the fallopian tube: two case reports

A 52-year-old woman volunteered to participate in a multi-modal screening programme for ovarian cancer in asymptomatic postmenopausal women at The London Hospital (Jacobs et al. 1988). She had had one child but was now postmenopausal. Serum CA 125 was determined using the Abbot Laboratory CA 125 radioimmunoassay. An abnormal level was defined as >30 U/ml (Bast et af. 1983). Her initial CA 125 level in venous blood was elevated at 43.7 U/ml. Consequently real-time pelvic ultrasonography (transabdominal) was performed in accordance with the study protocol. This showed both ovaries to be of normal volume and morphology. No abnormality was noted. She was followed up by 3 monthly serum CA 125 measurements, again in accordance with the study protocol. The serum level remained mildly elevated at 32.2, 35 and 38 U/ml at 3, 6 and 9 months respectively. At 11 months after her initial CA 125 measurement she developed lower abdominal discomfort. A repeat ultrasound scan identified a 7 cm solid left-sided pelvic mass. At laparotomy she was found to have a carcinoma of the left fallopian tube and a hysterectomy, bilateral salpingo-oophorectomy and omentectomy was performed. Histological examination confirmed a poorly differentiated papillary adenocarcinoma of the left fallopian tube (Stage I).