Elevation of multiple serum markers in patients with stage I ovarian cancer.

BACKGROUND: The high overall mortality from ovarian cancer (> 60%) relates, in part, to delays in diagnosis. When ovarian cancer is detected in stage I (International Federation of Gynecology and Obstetrics staging), up to 90% of patients can be cured. Transvaginal sonography can detect early-stage disease with great sensitivity, but it is expensive and lacks specificity. Although serum marker assays could provide a less expensive and more convenient initial screening test, the sensitivity of assays varies. Measurement of serum CA 125 in conjunction with ultrasound screening as a second-line test confers high specificity but detects only about one half of early stage ovarian carcinomas. PURPOSE: The purpose of this retrospective study was to determine whether assays of multiple serum markers would improve sensitivity by detecting a higher percentage of stage I ovarian cancers than the CA 125 assay alone. METHODS: Using immunoradiometric assays, we measured preoperative serum levels of CA 125 tumor-associated antigen, macrophage colony-stimulating factor (M-CSF), and OVX1 in 46 patients with stage I ovarian cancer of different histologies and 237 patients with benign pelvic masses. We also assayed sera from 204 apparently healthy women who had participated in a screening trial and remained free from cancer at 1 year of followup. All specimens were obtained from cryopreserved aliquots. Marker levels were considered to be elevated when levels of CA 125 were greater than 30 U/mL, M-CSF levels were greater than 3.1 ng/mL, or OVX1 levels were greater than 12.1 U/mL. RESULTS: At least one of the serum markers was elevated in 98% of patients with stage I ovarian cancer; CA 125 levels were elevated in 67%. By the same criteria, 11% of healthy individuals and 51% of patients with benign pelvic masses had at least one elevated marker value. Thus, the sensitivity of the combination of assays for the three serum markers was significantly greater than the sensitivity of the CA 125 assay (P < .0005) and specificity was moderate. CONCLUSION: A panel of these three tumor markers can identify early-stage ovarian cancer with extremely high sensitivity and moderate specificity. IMPLICATIONS: Elevation of one or more serum markers should be evaluated further as an indication for transvaginal sonography in apparently healthy women. Such a strategy might substantially reduce the expense and improve the specificity of screening compared to the use of ultrasound alone. Prospective studies with a large cohort of patients at high risk for ovarian cancer will be required to confirm these findings.

Strategies for improving the specificity of screening for ovarian cancer with tumor-associated antigens CA 125, CA 15-3, and TAG 72.3.

OBJECTIVE: To assess different strategies for improving the specificity of screening for ovarian cancer with tumor-associated antigens, including concomitant measurement of multiple tumor markers and serial measurement of CA 125. METHODS: A combination of CA 125, CA 15-3, and TAG 72.3 was evaluated in serum samples from 217 of 1010 apparently healthy postmenopausal women who had participated in a study of screening for ovarian cancer and who had a serum CA 125 level of 20 U/mL or greater. In addition, serial serum CA 125 levels were determined in 30 women with an initially elevated CA 125 level (30 U/mL or more) and 30 women with a CA 125 level less than 30 U/mL. RESULTS: The specificity of CA 125 at upper limits of 30 and 50 U/mL was increased from 97.0 and 99.5%, respectively, to 98.9 and 99.9% when a positive test was defined as an elevated serum CA 125 level in combination with either a CA 15-3 greater than 30 U/mL or a TAG 72.3 greater than 10 U/mL. Definition of a positive result as a serum CA 125 level greater than 50 U/mL at the initial test and greater than 30 U/mL at 3-month follow-up achieved a specificity of 99.6%. CONCLUSION: Levels of specificity suitable for screening asymptomatic postmenopausal women can be achieved using tumor-associated antigens measured serially or in combination. Further studies are required to determine the sensitivity of these strategies for preclinical ovarian cancer.

Ovarian cancer identified through screening with serum markers but not by pelvic imaging.

Woolas RP, Oram DH, Jeyarajah AR, Bast RC Jr, Jacobs IJ. Ovarian cancer identified through screening with serum markers but not by pelvic imaging. This study evaluated the possible role of 3 additional tumor markers to CA 125 among postmenopausal volunteers participating in a sequential multimodal ovarian cancer screening study. In 82 asymptomatic women the finding of a serum CA 125 level of > 30 U/ml precipitated pelvic ultrasound examination. Levels of CA15-3, CA72-4 and CA19-9 were subsequently determined in sera stored from the time of the CA 125 assay. Following ultrasound 29 women underwent surgery for benign conditions. The remaining 53 women underwent 2 years of surveillance. In 5 of these women a diagnosis of ovarian cancer was established between 6 and 10 months after their initial investigation. Elevated levels of at least one of the 3 additional tumor markers were present in the serum, prior to ultrasound abnormalities being detected, in 4 (80%) of the women who developed cancer. At least one of this 3-marker panel was elevated in 29% of the 48 women who have not developed cancer and 14% of the 29 women undergoing surgery for benign conditions. Information complementary to pelvic ultrasound examination for the preclinical detection of ovarian cancer could be obtained through multiple marker assay. Coordinated elevated serum levels of tumor markers could increase the sensitivity of this sequential screening protocol.

Risk of diagnosis of ovarian cancer after raised serum CA 125 concentration: a prospective cohort study.

OBJECTIVE: To determine the risk of invasive epithelial ovarian cancer and fallopian tube cancer associated with a raised concentration of the tumour marker CA 125 in asymptomatic postmenopausal women. DESIGN: Serum CA 125 concentration was measured annually in study participants for one to four years. Participants with a concentration > or = 30 U/ml were recalled for abdominal ultrasonography. Follow up was by annual postal questionnaire. SETTING: General practice, occupational health departments, ovarian cancer screening unit in a teaching hospital. SUBJECTS: 22,000 volunteers, all postmenopausal women > or = 45 years of age; recruited between 1 June 1986 and 1 May 1990. INTERVENTION: Surgical investigation if the ultrasound examination was abnormal. MAIN OUTCOME MEASURES: Cumulative and relative risk of developing an index cancer (invasive epithelial cancer of the ovary or fallopian tube) after a specified CA 125 result. RESULTS: 49 index cancers developed in the study population during a mean follow up of 6.76 years. The overall cumulative risk of developing an index cancer was 0.0022 for the entire study population and was lower for women with a serum CA 125 concentration < 30 U/ml (cumulative risk 0.0012) but was appreciably increased for women with a concentration > or = 30 U/ml (0.030) and > 100 U/ml (0.149). Compared with the entire study population the relative risk of developing an index cancer within one year and five years was increased 35.9-fold (95% confidence interval 18.3 to 70.4) and 14.3-fold (8.5 to 24.3) respectively after a serum CA 125 concentration > or = 30 U/ml and 204.8-fold (79.0 to 530.7) and 74.5-fold (31.1 to 178.3) respectively after a concentration > or = 100 U/ml. CONCLUSION: CA 125 is a powerful index of risk of ovarian and fallopian tube cancer in asymptomatic postmenopausal women.

Radical trachelectomy in early stage carcinoma of the cervix: outcome as judged by recurrence and fertility rates.

The recurrence and fertility rates in 30 women undergoing radical trachelectomy for early stage invasive cervical cancer at St Bartholomew's and Royal Marsden Hospital were reviewed. There were no recurrences, and the mean follow up was 23 months (range 1-64 months). Of 13 women trying to have a baby, eight had conceived with a total of 14 pregnancies and nine live births. Two were still trying and three were experiencing sub-fertility. There were seven premature deliveries and one late miscarriage. Six of the preterm births and the late miscarriage were associated with prelabour spontaneous rupture of membranes. This conservative yet locally radical procedure for a highly selected group of women who wished to preserve their fertility appears to offer a safe alternative to radical hysterectomy in early invasive cervical cancer.

Radical trachelectomy: a way to preserve fertility in the treatment of early cervical cancer.

In the Centenary year of Wertheim's hysterectomy for the treatment of invasive cervical cancer, it is appropriate to look at less radical methods of managing early stage disease. Radical trachelectomy with pelvic lymphadenectomy is a conservative but locally radical procedure, preserving the corpus uteri and therefore fertility potential. The first 10 cases in a pilot study are presented. One patient has required post-operative radiotherapy and another a completion radical hysterectomy. Three live births by caesarean section and three other pregnancies have resulted. Careful selection within strict criteria may allow this more conservative approach without compromising cure. These procedures should be carried out in referral centres with continuing follow up and review.

Stage III epithelial ovarian cancer: the role of maximal surgical reduction.

One hundred forty-two cases of ovarian cancer of epithelial origin treated at Georgetown University Hospital between 1974 and 1980 were analyzed. Seventy-five patients (52.8%) were found to have Stage III disease at the time of the initial laparotomy, and the purpose of this study was to assess the outcome of the management in this group of patients. In spite of an aggressive approach, complete tumor excision could only be affected in 13 of the 75 Stage III cases (17.3%). Residual disease of less than 2 cm was achieved in a further 8 cases (10.7%). The ability to perform complete tumor clearance bore no relationship to the grade of the tumor. The survival rate in the complete clearance group was 100% with a mean survival time of 45 months (range 10-90 months) and 10 of these patients have been shown to be free of disease by second-look laparotomy. The outcome in terms of survival and disease-free status in these two groups of patients was unaffected by various chemotherapy regimens and the only factor of importance appeared to be the success of the initial surgery in clearing the disease.

Differential diagnosis of ovarian cancer with tumour markers CA 125, CA 15-3 and TAG 72.3.

OBJECTIVE: To determine the accuracy of tumour associated antigens CA 125, CA 15-3 and TAG 72.3 in the differential diagnosis of benign and malignant pelvic masses and to compare the results with a previously defined risk of malignancy index (RMI). DESIGN: Retrospective analysis of samples collected during a prospective observational study. SETTING: Department of Obstetrics and Gynaecology, the Royal London Hospital and Duke University Medical Center. SUBJECTS: One hundred and forty-three consecutive patients undergoing surgery for an adnexal mass. METHOD: Tumour marker levels were determined by radio-immunoassay in stored serum samples obtained from 143 study subjects. RESULTS: The highest diagnostic accuracy of the tumour marker panel was achieved by defining a positive result as elevation of any two of CA 125 (> 30 u/ml), CA 15-3 (> 30 u/ml) and TAG 72.3 (> 10 u/ml), (sensitivity 66.7%, specificity 93.1%). Similar diagnostic accuracy could be achieved by CA 125 alone using an upper limit of 50 u/ml (sensitivity 66.7%, specificity 94.1%). Inclusion of CA 15-3 or TAG 72.3 in stepwise logistic regression analysis did not improve the discriminative performance of the RMI. CONCLUSION: The risk of malignancy index incorporating CA 125, menopausal status and ultrasound is superior to the panel of three tumour markers for pre-operative differential diagnosis of the pelvic mass.

Immunocytochemical and serological expression of CA 125: a clinicopathological study of 40 malignant ovarian epithelial tumours.

Elevated serum levels of the tumour-associated antigen CA 125 occur in more than 80% of cases of ovarian carcinoma. The antigen can be demonstrated in formalin-fixed tissue using the monoclonal antibody OC 125, which localizes it to the surface membrane or cytoplasm. This study was performed to determine the relationship between pre-operative serum levels of CA 125 and the subsequent immunocytochemical findings in the surgical specimen. Paraffin-wax embedded sections from 40 consecutive borderline and frankly malignant ovarian epithelial tumours were stained with OC 125. The pattern and distribution of immunostaining were investigated in relation to histological appearances. Serous tumours showed a 100% correlation between immunocytochemical findings and elevated serum levels of CA 125. Amongst the other histological types, correlation was less good; mucinous tumours and undifferentiated carcinomas showed a poor correlation. Immunostaining within tumours was heterogeneous and only loosely related to morphological appearances. Our finding suggests that, with the exception of serous tumours, immunolocalization of CA 125 is insufficiently sensitive to provide reliable clinical guidance to the likely value of serum CA 125 monitoring on follow-up.

Serum CA125 elevation and risk of clinical detection of cancer in asymptomatic postmenopausal women.

BACKGROUND: This study was undertaken to assess the correlation between CA125 elevation, a past history of cancer, and future risk of a diagnosis of cancer among asymptomatic postmenopausal women. METHODS: The subjects consisted of a study group of 771 women with elevated CA125 (> or =30 U/mL) and a control group of 771 women with CA125 <30 U/mL. They were selected from a prospective ovarian carcinoma screening trial of 22,000 postmenopausal women followed for a mean of 2269 days. RESULTS: Subjects in the study group were more likely to have a past history of cancer than subjects in the control group (odds ratio [OR] 2.31, 95% confidence interval [CI] 1.49-3.58). Much of the difference in cancer risk prior to CA125 testing was attributable to a past history of breast carcinoma (OR 2.53, 95% CI 1.45-4.42), but CA125 elevation did not predict recurrence of breast carcinoma. Subjects in the study group were also more likely to develop cancer in the future (OR 2.53, 95% CI 1.61-3.97). This difference was due to an increased risk of gynecologic cancer (OR 30.09, 95% CI 4.09-221.59). CA125 elevation was not associated with an increase in the future risk of developing breast carcinoma (OR 1.19, 95% CI 0.53-2.66) or nongynecologic cancer (OR 1.43, 95% CI 0.86-2.36). CONCLUSIONS: Elevated CA125 in asymptomatic postmenopausal women is not a predictor of nongynecologic cancer or recurrence of cancer, and further investigation should be limited to the detection of gynecologic cancers.

Serum CA 125 in a pregnancy generated by ovum donation.

Serum CA 125 was measured by radioimmunoassay during the first trimester at intervals of 2 weeks in a woman with Turner's syndrome, who conceived following ovum donation from a healthy anonymous donor. Serum CA 125 concentrations were lower than or at the 10th percentile of the normal range. These findings imply that CA 125 may be secreted from the ovary in the first trimester, or produced at another site in response to stimuli from the ovary.

Endocrine changes and symptomatology after oophorectomy in premenopausal women.

The symptomatic and endocrine changes following hysterectomy and bilateral oophorectomy have been studied in 100 patients, 1 to 31 years after surgery. The most frequent symptoms at the time of interview were depression (62 patients), insomnia (48 patients), loss of libido (46 patients) and dyspareunia (38 patients). Vasomotor symptoms were recorded in 28 patients. Although 94 patients claimed that hot flushes were the first symptomatic changes noticed, 60 had complete relief from these symptoms within 6 months of surgery; 34 patients had no symptoms and only 4 patients were taking oestrogen therapy at the time of interview. Plasma oestradiol and testosterone levels were 78 per cent and 27 per cent respectively below the mean values of day 1 to 10 of the menstrual cycle, similar to those found at comparable years after a normal menopause. The plasma FSH level was about 14 times and the plasma LH level about twice the respective preoperative value. Unlike after the normal menopause, these gonadotrophin levels did not show any decline with increasing age. There was no correlation between plasma hormone levels and the presence of vasomotor symptoms or depression.

Effect of hormone replacement therapy on glucose tolerance in postmenopausal women.

Oral glucose tolerance tests were performed on 50 symptomatic postmenopausal women before and after three months of hormone replacement therapy. All patients were randomly allocated to one of five groups treated with various synthetic or so-called naturally occurring oestrogens. Therapy produced a significant deterioration of carbohydrate tolerance with sequential preparations containing 100 microgram of ethinyl oestradiol or graduated doses of mestranol up to 50 microgram. The conjugated equine oestrogen (1.25 mg daily) and oestrogen valerate (2 mg daily) treated groups did not show abnormal glucose tolerance. The decreased glucose tolerance may be due as much to dosage levels as to any metabolic characteristics of the various oestrogens prescribed.

Early diagnosis of ovarian cancer.

In spite of recent therapeutic advances, earlier diagnosis seems to be the best hope of significantly improving the prognosis in ovarian cancer. This paper discusses the various screening modalities available, and presents the interim results of one large screening project.

MR imaging of uterine sarcomas.

OBJECTIVE: The MR imaging appearances of uterine sarcomas are not well described in the literature. We describe the MR imaging features of uterine sarcomas. MATERIALS AND METHODS: MR images from all patients with histologically proven uterine sarcomas scanned between 1993 and 2000 were reviewed. Tumor size, its relationship to the uterus, signal characteristics, and enhancement pattern after IV injection of gadolinium were noted. RESULTS: Twenty-five scans from 22 patients were reviewed. Findings from the scans included 11 leiomyosarcomas, five mixed müllerian tumors, two rhabdosarcomas, and four endometrial stromal sarcomas. Two patterns of disease were observed, including a characteristic large heterogenous pelvic mass (n = 17) and an endometrial mass indistinguishable from endometrial carcinoma (n = 8). On T2-weighted images, the large masses were characteristically of low or intermediate background signal intensity with pockets of very high T2 signal. The areas of high T2 signal corresponded to cystic necrosis in the tumor. Pockets of high T1-weighted signal corresponded to hemorrhage. Gadolinium enhancement was present in the solid components of all tumors. This pattern was observed in all recurrent sarcomas. Some correlation was shown between the histologic subtypes and the MR imaging appearances. CONCLUSION: Uterine sarcomas show two patterns on MR imaging. The most common presentation is a large heterogenous mass. However, sarcomas can mimic endometrial carcinoma.

Increased mortality in postmenopausal women with serum CA125 elevation.

OBJECTIVES: Serum CA125 is used in monitoring treatment and detecting recurrence in ovarian cancer (OC). We have also shown that CA125 can be used with ultrasound for the early detection of OC. However, physiological, benign, and malignant conditions are also associated with CA125 elevation. The aim of the study was to determine the prognostic implications of CA125 elevation in asymptomatic postmenopausal women. METHODS: The study involved 771 volunteers in an OC screening trial of 22,000 women who had elevated serum CA125 levels (>/=30 U/ml). The control group consisted of an equal number of volunteers with normal levels. Survival was analyzed from the first point of CA125 elevation. Univariate analyses utilized the log-rank chi2 test. A logistic model was constructed for the multivariate analyses. RESULTS: The mean duration of follow-up was 1614 days (SD 897 days). Eighty-four women died (elevated CA125 group-62, control group-22). Univariate analyses showed that mortality in the elevated CA125 group was significantly greater (log-rank chi2 = 23.556, P < 0.0001, RR = 2.76), even when preexisting morbid conditions were excluded (log-rank chi2 = 14.644, P = 0.0001, RR = 2.4). Multivariate analysis showed that CA125 elevation, age (>60 years), and a prior history of cancer were associated with a poor prognosis. CONCLUSIONS: Serum CA125 elevation is associated with a significantly increased risk of death from all causes in the next 5 years. These findings may have implications for asymptomatic postmenopausal women with CA125 elevation.

The distribution of CA 125 in the reproductive tract of pregnant and non-pregnant women.

Investigation of serum and tissue homogenates obtained from first, second and third trimester pregnancies, and from non-pregnant women, has provided further insight into the possible origin of the CA 125 antigen. Serum CA 125 levels were higher in the first trimester (median 53.6 U/ml, range 15.6-268.3 U/ml) than in non-pregnant women (median 19.3 U/ml, range 7.2-27.0 U/ml) and later in pregnancy (second trimester: median 18.5 U/ml, range 12.0-25.1 U/ml, third trimester: median 19.2 U/ml, range 16.8-43.8 U/ml) (P less than 0.05) but were two orders of magnitude less than in second trimester amniotic fluid (median 4825 U/ml, range 3200-9300 U/ml). Fetal serum CA 125 activity was consistently less than 20 U/ml. The highest tissue levels of CA 125 were detected in first trimester decidual homogenate (median 4547 U/100 mg, range 340.4-20 851 U/100 mg) and were greater than in non-pregnant endometrium (median 388 U/100 mg, range 100.9-3341 U/100 mg) (P less than 0.01) and term decidua (median 116 U/100 mg, range 32.7-449.9 U/100 mg) (P less than 0.01). These observations suggest that CA 125 is synthesized by normal endometrium and decidua and that increased CA 125 activity during pregnancy is of decidual origin.

Hormonal profiles after the menopause.

The endocrinological changes of the climacteric have been defined by studying the concentrations of follicle-stimulating hormone (FSH), luteinising hormone (LH), androstenedione, testosterone, oestrone, and oestradiol in 60 normal postmenopausal women of different menopausal ages. The women were studied in six groups, according to the number of years since their menopause. One year after the menopause androstenedione, oestrone, and oestradiol concentrations were reduced to about 20% of the values recorded during the early proliferative phase of the menstrual cycle. At the same time the mean concentration of FSH had risen by a factor of 13-4 and that of LH by a factor of 3-0. Concentrations of both gonadotrophins reached a peak of 18-4 and 3-4 times the proliferative phase value respectively after two to three years, and then gradually declined in the next three decades to values that were 40-50% of these maximal levels. Testosterone concentrations remained mostly in the normal range for premenopausal women but were depressed to 60% of these levels two to five years after the menopause, and the mean androstenedione levels showed a significant increase in the same group of women. The concentrations of both oestrone and oestradiol remained consistently low for 10 years after the menopause, but oestradiol concentrations inexplicably increased in the last two decades, with levels at the lower end of normal range for reproductive women in six patients.

Long-term follow-up of gonadotrophin-releasing hormone analog treatment for recurrent endometrial cancer.

To test the antitumor effect of gonadotrophin-releasing hormone (GnRH) analogs, 32 consecutive patients with recurrent endometrial cancer that had progressed through conventional treatments were entered into an open observational trial of treatment with this class of compounds. Patients recruited had progressive, symptomatic, and measurable disease. Treatment was with monthly subcutaneous injections of GnRH analog. Measurements of gonadotrophins, sex hormones, and tumor dimensions were made together with repeat biopsy when possible to assess response to treatment. An objective response was seen in nine patients (28%, 95% CI 13-43%). Responses were seen within the first 2 months of treatment and included pelvic as well as distant sites of recurrence. Significantly greater response rates were seen in previously irradiated sites when compared with nonirradiated sites of recurrence (0.01 > P > 0.001). There was no significant difference between the response in patients with G3 lesions compared with patients with G1/G2 lesions (P > 0.5). Response did not correlate with previous progestogen exposure. No evidence of disease flare or drug toxicity was observed. GnRH analogs have a significant and durable antitumor effect in recurrent endometrial cancer which warrants further examination in comparison with progestogens.