Use of CA 125 to monitor patients with ovarian epithelial carcinomas

The CA 125 radioimmunoassay has been increasingly used to monitor the course of patients with ovarian epithelial carcinomas. The purpose of this report is to describe our experience in the use of this assay and to better define its clinical utility. Fifty-one patients had serum CA 125 follow-up during primary chemotherapy. All 51 patients demonstrated either a normal CA 125 level at the completion of chemotherapy or a substantial fall in CA 125 values with treatment. In 48 of 51 patients, the drop in CA 125 levels was temporally related to the clinical regression or remission of tumor. Forty of these patients underwent second-look laparotomy; 23 patients (58%) had residual disease. A total of 45 patients had serum CA 125 determinations at the time of second-look laparotomy. Eight patients with microscopic disease and 11 of 18 patients with gross residual disease had a "negative" (less than 35 U/ml) CA 125 level. The predictive value of an elevated CA 125 level was 1.00. However, the predictive value of a negative value was only 0.50. Hence, a negative CA 125 level cannot be a substitute for a second-look laparotomy. Only 7 of 18 patients (39%) with gross residual disease at second-look surgery had an elevated CA 125 level. Patients with an elevated CA 125 and gross residual tumor at the second-look laparotomy uniformly demonstrated large, bulky disease. Furthermore, the survival of patients with gross residual disease at second-look laparotomy correlated with the preoperative CA 125 value. Serum CA 125 determinations also show promise in the follow-up of patients with a negative second-look laparotomy. The serum CA 125 level from patients with a "negative" second-look laparotomy can become elevated months before recurrent disease is appreciated.     

Influence of human antimurine antibody on CA 125 levels in patients with ovarian cancer undergoing radioimmunotherapy or immunoscintigraphy with murine monoclonal antibody OC 125

Human antimurine antibody responses interfere with CA 125 antigen determinations by crosslinking the murine antiovarian carcinoma monoclonal antibody OC 125 with the second murine radiolabeled antibody used in the CA 125 radioimmunoassay. Serial CA 125 levels in 22 patients with epithelial ovarian carcinoma undergoing either radioimmunotherapy or radioimmunoscintigraphy with iodine 131-labeled F(ab')2 fragments of OC 125 were followed up for up to 96 weeks after infusion. Fourteen radioimmunoscintigraphy patients received 131I-labeled monoclonal antibody by the intraperitoneal (n = 5) or intravenous (n = 9) route: 10 of 14 had sera drawn at appropriate time points for human antimurine antibody detection; 8 of 10 had 1.3- to 363-fold increases in CA 125; 4 of 8 had detectable human antimurine antibody (18.5 to 22 and 575 to 36 micrograms/ml). Eight radioimmunotherapy patients received 131I-labeled monoclonal antibody by the intraperitoneal route: 8 of 8 displayed an apparent 4.8- to 3725-fold increase in CA 125 levels within 7 to 42 days after monoclonal antibody infusion; 6 of 8 had detectable human antimurine antibody (13 to 4 and 319 to 31 micrograms/ml). Adsorption of immunoglobulin G resulted in a 21% to 98% reduction in CA 125 antigen levels in 4 of 4 patients tested. In patients with demonstrable human antimurine antibody, CA 125 antigen levels obtained by the clinical CA 125 radioimmunoassay are spuriously elevated.     

Tumour-associated antigen CA 125 in patients with ovarian cancer

The serum levels of antigen CA 125 expressed by epithelial ovarian carcinoma were measured in 27 postmenopausal women with ovarian tumours and in 16 controls. Increased serum levels of CA 125 were found in nine (75%) out of 12 patients with ovarian cancer; in three with stage I disease levels were not elevated. No significant difference was found in the concentration of CA 125 detected in peripheral or ovarian venous blood. Decreased antigen levels were found 6-30 weeks after radical operation and cytostatic chemotherapy in the ovarian cancer group. The results indicate the value of measuring CA 125 as a tumour marker in the follow-up of ovarian cancer.     

Tumour-associated antigen CA 125 in patients with ovarian cancer

Summary. The serum levels of antigen CA 125 expressed by epithelial ovarian carcinoma were measured in 27 postmenopausal women with ovarian tumours and in 16 controls. Increased serum levels of CA 125 were found in nine (75%) out of 12 patients with ovarian cancer; in three with stage I disease levels were not elevated. No significant difference was found in the concentration of CA 125 detected in peripheral or ovarian venous blood. Decreased antigen levels were found 6–30 weeks after radical operation and cytostatic chemotherapy in the ovarian cancer group. The results indicate the value of measuring CA 125 as a tumour marker in the follow-up of ovarian cancer.     

Human anti-murine antibody responses in ovarian cancer patients undergoing radioimmunotherapy with the murine monoclonal antibody OC-125

Human anti-murine antibody (HAMA) responses were monitored in 23 patients with recurrent or persistent epithelial ovarian carcinoma undergoing single-dose intraperitoneal radioimmunotherapy (RIT) with the murine monoclonal antibody OC-125. Sera of patients receiving escalating doses of OC-125 F(ab')2 (10-70 mg) radiolabeled with 18 to 141 mCi of iodine-131 were assayed for HAMA by a protein A-based radioimmunoassay. Overall, 70% of patients (16/23) developed HAMA within 10 to 46 days (median = 29) postinfusion, with peak values (23 +/- 6 to 325 +/- 10 micrograms/ml) at 32 to 102 days (median = 38). HAMA was undetectable prior to infusion in all cases and persisted up to 76 weeks. Of patients receiving a dose of 123 mCi or less, 80% (16/20) developed HAMA, whereas in the 140-mCi group, none of the three patients had detectable levels. Two patients in the 140-mCi group demonstrated dose-limiting bone marrow toxicity (severe thrombocytopenia and neutropenia). It is concluded that a single intraperitoneal dose of monoclonal antibody leads to a high incidence of HAMA production. The results also suggest that the likelihood of HAMA formation in patients who either had undergone recent chemotherapy or had received the highest dose of the radioimmunoconjugate is reduced. These observations may be of significance in designing multiple-dose therapy trials as HAMA has been demonstrated to decrease antibody-to-tumor binding and may potentially increase renal, hepatic, and hematologic toxicity associated with radioimmunotherapy.     

CA 125 in the follow-up of patients with ovarian cancer

Three hundred and ninety-five CA 125 serum values of 72 patients with ovarian cancer were correlated with the clinical status. With a threshold value of 35 U/ml we found true negative values in 85% and true positive values in 93%. No correlation between preoperative CA 125 values and tumor stage was noted at primary surgery. During follow-up, 17 women had marker values between 35 and 65 U/ml. Three out of 7 women in clinical remission showed a value greater than 65 U/ml at subsequent follow-up and developed recurrent disease. In 8 patients out of 20 re-laparotomies, tumors with a maximum diameter of greater than 2 cm were confirmed with a preoperative serum CA 125 concentration greater than 65 U/ml. Two out of 3 patients with a tumor diameter less than 2 cm at re-laparotomy revealed CA 125 serum concentrations less than 35 U/ml. A false positive CA 125 value was found in one patient without demonstrable active disease. The calculated doubling time of the CA 125 values ranged between 23 and 173 days; the median value was 67 +/- 47 days. After 6.2 +/- 1.3 doubling times death ensued.     

CA 125 in the follow-up of patients with ovarian cancer

The value of CA 125 measurement in the diagnosis and follow-up of ovarian cancer was studied in 102 patients. The CA 125 levels were elevated in 88% (322/365) of samples from 82 patients with clinical evidence of disease and in 14% (56/403) of samples from 58 patients without clinical evidence. Preoperative levels were elevated in 84% (44/52) of the patients, and in 100% of those with stage III and IV disease. In patients with non-mucinous tumors the preoperative levels were elevated in 95% of cases (38/40). CA 125 levels were significantly correlated with the course of disease in 88% (36/41) of patients whose tumor regressed, and in 87% (20/23) of those whose tumor progressed. Before second-look surgery of 48 patients, the sensitivity of the CA 125 test was 35% and the specificity was 86%. The results suggest that, although far from infallible, CA 125 is a useful marker for ovarian cancer. It is useful for monitoring the course of chemotherapy, but normal levels do not rule out the possibility of persistent or recurrent disease.     

Use of indium-111-labeled OC-125 monoclonal antibody in the detection of ovarian cancer

This is a preliminary study to evaluate the utility of using the monoclonal antibody (CO-125) labeled with indium-111 to image recurrences of ovarian cancer. This technique has been investigated in 23 patients with ovarian cancer and the results have been compared with blood OC-125 levels, CT scans, and findings at second-look surgery. Following infusion of 1 mg of F(ab')2 fragments (1-2 mCi 111In), quantitative SPECT and planar imaging was obtained daily for 72 hr along with analysis of serum. The nuclear medicine scans of the tumor site recurrences were technically excellent. When compared to second-look laparotomy, there were 2 true negatives, 2 false positives, 14 true positives, and 2 false negatives by nuclear imaging. CT scans correlated less well with surgery, but serum OC-125 levels correlate more closely with nuclear scans and second-look surgery. Those with multiple small metastatic implants showed a pattern of diffuse uptake which increased with time, whereas those with nodal or larger recurrences showed a more focal uptake. The combination of favorable biodistribution and positive images, especially in patients with normal antigen levels and negative CT scans, suggests a role for OC-125 monoclonal antibody imaging in their clinical management. However, further investigation is needed to determine whether nuclear scans can replace second-look surgery. If it can show that enough 111In-labeled antibody accumulates in the tumor site to justify radioimmunotherapy, then 90Y (a pure beta emitter) could be exchanged for 111In. This is potentially a method of radioimmunotherapy for recurrent ovarian carcinoma.     

Chemotherapy-induced changes of CA 125 in patients with epithelial ovarian cancer

OBJECTIVES: CA 125 is a tumor marker widely used to diagnose, monitor, and follow-up women with epithelial ovarian cancer, as the marker is well related to the amount of vital tumor cells. However, CA 125 before the operation or during the first 2 courses of chemotherapy does not provide enough information concerning survival to serve as a prognostic marker. The present investigation was inspired by studies describing a paradoxical increase of tumor markers (CEA, CA 125, and CA 15-3) in the days after chemotherapy of women with breast cancer. If CA 125 increases within days after chemotherapy, the increase may be caused by death of the cancer cells. It was therefore speculated if a CA 125 spike may serve as an early prognostic parameter. The aim of the present investigation was to evaluate if CA 125 increases within days after the first course of chemotherapy of women with ovarian cancer. PATIENTS: Twenty women with epithelial ovarian cancer were included in the study. CA 125 was measured in each woman on day 0 (the day of, but before initiation of chemotherapy) and 1, 3, 5, 7, 9, and 14 days after chemotherapy. RESULTS: One woman was excluded due to normal CA 125 values. The remaining 19 patients displayed a significant decrease in CA 125 during the 14-day period after chemotherapy. CONCLUSION: In the present study, no chemotherapy-induced increase of CA 125 within the first 14 days after chemotherapy could be demonstrated.     

CA 125 in monitoring chemotherapy of the patients with ovarian cancer

Changes in CA 125 antigen concentration and serum half-life were determined in 63 women with ovarian carcinoma during chemotherapy following various types of surgery. Concentration of CA 125 in serum correlated with the degree of clinical advancement of the tumor, 20.00 and 688.84 U per ml at stages I, II, and IV, respectively, and with remaining tumor mass, despite chemotherapy, serum CA 125 level rose after exploratory surgery. Estimation of CA 125 levels proved less useful in the mucinous type of ovarian carcinoma. The treatment scheme including Cisplatinum reduced CA 125 levels most effectively correlated with good clinical response to the therapy. Testing the half-life time appeared to provide a good prognostic index, 6.25 +/- 2.08 days after radical surgery and 44.87 +/- 26.5 days after probatory laparotomy.     

A pilot phase 2 study of oregovomab murine monoclonal antibody to CA125 as an immunotherapeutic agent for recurrent ovarian cancer

This prospective, open-label, pilot phase 2 study examined the clinical and immunologic effects of oregovomab (OvaRex) in heavily pretreated patients with recurrent ovarian cancer (OC). Thirteen women were administered intravenous oregovomab (2 mg) at weeks 0, 2, 4, 8, and 12, followed by quarterly doses for up to 2 years or disease progression. Concomitant chemotherapy was not permitted. Eligibility criteria included recurrence after one or more platinum-based chemotherapy regimens, CA125 >35 U/mL, evaluable or measurable disease. Tumor burden was evaluated by physical or radiologic methods pretreatment, weeks 12, 24, and every 24 weeks thereafter. Immune responses, including antibodies and T cells to oregovomab and CA125, were demonstrated in over half the patients. Stabilization of disease and survival >2 years was observed in 3 of 13 patients and coincided with robust immune responses. Shrinkage of marker lesions was not observed; however, four patients showed decreases in CA125 levels. Treatment was well tolerated without serious adverse events or discontinuations due to therapy. This pilot study supports immunologic activity and safety of oregovomab in recurrent OC. Further study of this agent in the consolidation and adjuvant setting is ongoing to establish its clinical utility.     

CA125 in peritoneal fluid of ovarian cancer patients.

The presence of CA125 was assessed in peritoneal fluid from 70 patients with ovarian cancer and 32 control patients. The follow-up period ranged from 39 to 89 months (median, 56 months). The cutoff for normal peritoneal fluid CA125 levels was determined to be 250 U/ml. A positive correlation between the serum and peritoneal fluid CA125 levels was observed (P less than 0.001). Peritoneal fluid levels were higher than serum levels in all patients. Patients with evidence of active ovarian cancer showed higher peritoneal fluid CA125 levels than the control patients (P less than 0.001). Peritoneal fluid CA125 levels correlated inversely with survival (P = 0.004). The peritoneal fluid CA125 levels were higher in patients with bulky tumor than in those with small (less than 1 cm) tumors (P less than 0.001). Eight out of twenty-six patients with active cancer and available peritoneal cytology had a negative peritoneal cytology. Three of these patients showed elevated peritoneal fluid levels. Three patients out of twenty-four showed elevated peritoneal fluid CA125 levels at second-look laparotomy. These 3 patients had negative biopsies at second-look surgery, but relapsed during the observation period. At second-look laparotomy an elevated peritoneal fluid CA125 level may imply a bad prognosis, but a normal level does not exclude the presence of disease.     

Daunorubicin conjugated to a monoclonal anti-CA125 antibody selectively kills human ovarian cancer cells

The present study was designed to test the in vitro efficacy for human ovarian cancer cells of daunorubicin (DNR) conjugated to a monoclonal antibody (OC125). The OC125 antibody specifically binds to the antigenic protein CA125 from human ovarian carcinoma. New analogs of DNR containing various linker groups were conjugated to mouse monoclonal anti-CA125 antibody (DNR-OC125); nonspecific murine IgG1 (DNR-IgG1); or bovine serum albumin (DNR-BSA). The DNR-protein conjugates were all stable for several days in neutral solutions at room temperature. The DNR-OC125 conjugates selectively killed dividing cell populations but not nondividing cell populations of two human ovarian cancer cell lines (SK-OV-3 or OVCAR-3) that express the CA125 antigen. Equivalent concentrations of DNR-IgG1 or DNR-BSA conjugates were neither toxic to the dividing nor the nondividing populations of SK-OV-3 or OVCAR-3 cells. Only those DNR-protein conjugates linked to OC125 were cytotoxic to dividing cell populations of both cell lines. This indicates that cytotoxicity is dependent on OC125 antibody-CA125 antigen binding which concentrates DNR on the ovarian cancer cells. We advance the hypothesis that following antibody-antigen binding, DNR is released from the conjugate and it intercalates in DNA by a mechanism similar to that of the unmodified DNR. The new DNR-OC125 conjugate may be useful for delivering DNR to ovarian tumors that express the CA125 antigen because the drug-antibody conjugates (1) retain the cytotoxic characteristics of the unmodified drug: (2) specifically kill the human ovarian cancer cells that express the CA125 antigen; and (3) are completely stable for days in neutral solutions at room temperature.     

CA 125 serum levels correlated with second-look operations among ovarian cancer patients

CA 125, which is an antigenic determinant expressed by many epithelial ovarian cancers, is measured in serum using a solid phase immunoradiometric assay. Sera from 55 patients who were in clinical remission and underwent a second-look operation to assess disease status after chemotherapy were studied prospectively. All patients had the CA 125 assay performed within one week before their second-look operation. Twenty-four patients (44%) had no histologic or cytologic evidence of disease, seven patients (13%) had microscopic disease, 13 patients (24%) had disease measuring 1 mm to 1.5 cm, and ten patients (18%) had disease greater than or equal to 1.5 cm in maximum tumor dimension. None of the 24 patients with a negative second-look operation had a positive CA 125 antigen level (greater than or equal to 35 U/mL), compared with six of 20 patients (30%) with less than 1.5 cm disease, and six of ten (60%) with greater than or equal to 1.5 cm disease (P less than .0001). All 12 patients with an elevated CA 125 antigen level (greater than or equal to 35 U/mL) had disease discovered at their second-look operation. Thus, in this setting the predictive value of a positive CA 125 titer (greater than or equal to 35 U/mL) was 100%. The predictive value of a negative CA 125 antigen level (less than 35 U/mL) was 56%, ie, the test did not exclude the presence of disease in 44% of patients with a positive second look. The maximum tumor size associated with at least one prior negative antigen level was 1.9 cm.(ABSTRACT TRUNCATED AT 250 WORDS)     

A new monoclonal antibody (SH-9) recognizes the low molecular mass of ovarian cancer antigen CA125]

The SHIN-3 cell line producing CA125 was established from an ovarian cancer patient. Using the SHIN-3 cell line, we found that the low-molecular-mass antigen (about 50 KDa) might be the main antigenic determinant in CA125-immunoreactive species. A new monoclonal antibody to this low-molecular-mass was raised to examine a new cancer associated antigen by a hybridoma technique. Using enzyme linked immuno sorbent assay, ten clones were selected from among 398 clones. Two clones were IgG1 and eight were IgM. By immunostaining (ABC assay), a new antibody (named SH-9) reacted with normal pulmonary bronchus and uterine cervical glands. No positivity, however, was observed in endometriosis (adenomyosis). In tumorous lesions of ovary, SH-9 antibody reacted specifically with mucinous cystadenoma-benign, borderline or malignant. However, no positivity was found in serous cystadenocarcinoma. In any other carcinomas, only lung cancer (adenocarcinoma, squamous cell carcinoma) showed a clear positivity. Immuno blotting analysis showed that SH-9 antibody recognized a low molecular mass. Therefore, SH-9 is seen to be an extremely unique antibody when compared with OC125 biochemically and histochemically.     

Cancer antigen CA 125 in ovarian cancer

AIM: To estimate the diagnostic and prognostic value, pathological and clinical correlation of cancer antigen 125 (CA125) in ovarian cancer (OC). Retrospective analysis was done of 350 patients who were operated for OC in years 1990-2001 in Gynecology Clinic MU of Gdansk. We analyzed those before primary operation (PO) and second look laparotomy (SLL). Chi 2 and t-Student tests were used. RESULTS: Before PO 18% OC patients had CA125 less than 35 and 43.8% more than 600 U/ml, for benign tumors it was 59.9 and 1.1 respectively (p < 0.001). 56.2% with complete remission and 43.8% with progress disease in SLL had normal values of antigen before the operation. There were 32 patients who had CA125 > 600 before SLL and all of those had progress disease. The positive and negative predictive value of CA125 before SLL were 0.94 and 0.56 respectively. Cytoreduction with no macroscopic disease was achieved in 45% of patients with CA125 < 600 U/ml before PO, and it was 19.2% for those with antigen > 600 (p = 0.001). We looked for differences of CA125 levels depending on clinical and pathological data. According to our results only histology (p = 0.02) and clinical stage (p = 0.02) influenced CA 125 levels. CONCLUSIONS: There is a good correlation between elevated levels of CA125 and state of the disease in SLL, and we consider SLL as obligatory to perform as there is a low negative predictive value of CA125. The CA125 before primary operation has prognostic significance to possibility of optimal cytoreduction.     

A CA125 score as a prognostic index in patients with ovarian cancer

Summary Due to its high specificity (90%) and sensitivity (86%) measurement of CA125 has become well-established in patients with epithelial ovarian cancer. We have formulated a CA125 prognostic score and examined its validity as an additional prognosis index. This score is composed of two CA125 values (one determined preoperatively and one 1 month after operation). CA125 serum levels of 0–64 IU/ml received 1 point, levels of 65–299 IU/ml were given 2 points, and those >300 IU/ml were given 3 points. These points are added to produce the CA125 prognostic score. Statistical comparison demonstrated that patients with scores of 2 or 3 had a significantly (P=0.0005) better prognosis than patients with scores of 4, 5 or 6. The classical prognostics features such as the FIGO stage, residual tumor mass and ascites were found to correlate with the CA125 prognostic score.     

CA 125 levels in patients with hypoestrogenic ovarian failure

The source of CA 125 in the sera of women is not known. Serum CA 125 concentrations were measured in 36 women with hypoestrogenic ovarian failure of whom 30 had hyper-(group A), 6 had hypo- or normogonado-tropic amenorrhea (group B). Group A consisted of 16 women with streak gonad syndrome, 6 with rudimentary ovary syndrome, 5 with premature menopause syndrome and 3 with gonadoblastoma. Serum CA 125 levels were normal in 34 patients irrespective of the presence of associated sex chromosome anomalies, and their mean values did not differ significantly from those of the 9 age-matched controls. We also measured normal CA 125 values in 2 females with müllerian agenesis. These data indicate that the derivatives of müllerian ducts do not contribute significantly to the presence of CA 125 in the sera of nonmenstruating adult women, and that the abnormalities of the X chromosome do not seem to influence CA 125 levels.