George J. Olt

Phase III Study of Cisplatin With or Without Paclitaxel in Stage IVB, Recurrent, or Persistent Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group Study

PURPOSE To determine whether cisplatin plus paclitaxel (C+P) improved response rate, progression-free survival (PFS), or survival compared with cisplatin alone in patients with stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix. PATIENTS AND METHODS Eligible: patients with measurable disease, performance status (PS) 0 to 2, and adequate hematologic, hepatic, and renal function received either cisplatin 50 mg/m2 or C+P (cisplatin 50 mg/m2 plus paclitaxel 135 mg/m2) every 3 weeks for six cycles. Tumor measurements and quality-of-life (QOL) assessments were obtained before each treatment cycle. RESULTS Of 280 patients entered, 6% were ineligible. Among 264 eligible patients, 134 received cisplatin and 130 received C+P. Groups were well matched with respect to age, ethnicity, PS, tumor grade, disease site, and number of cycles received. The majority of all patients had prior radiation therapy (cisplatin, 92%; C+P, 91%). Objective responses occurred in 19% (6% complete plus 13% partial) of patients receiving cisplatin versus 36% (15% complete plus 21% partial) receiving C+P (P = .002). The median PFS was 2.8 and 4.8 months, respectively, for cisplatin versus C+P (P < .001). There was no difference in median survival (8.8 months v 9.7 months). Grade 3 to 4 anemia and neutropenia were more common in the combination arm. There was no significant difference in QOL scores, although a disproportionate number of patients (cisplatin, n = 50; C+P, n = 33) dropped out of the QOL component, presumably because of increasing disease, deteriorating health status, or early death. CONCLUSION C+P is superior to cisplatin alone with respect to response rate and PFS with sustained QOL.

Regulation of growth of normal ovarian epithelial cells and ovarian cancer cell lines by transforming growth factor-β

OBJECTIVE The purpose of this study was to study the role of transforming growth factor-beta in regulation of proliferation of normal and malignant ovarian epithelial cells. STUDY DESIGN We examined production of and responsiveness to transforming growth factor-beta in primary monolayer cultures of epithelial cells from five normal human ovaries and in five ovarian cancer cell lines. RESULTS In normal ovarian epithelial cells, proliferation always was inhibited by transforming growth factor-beta (greater than 40%) (p less than 0.01). Among the cancer cell lines, proliferation of one was markedly inhibited (greater than 95%) (p less than 0.01), two were only modestly inhibited (15% to 20%) (p less than 0.05), and two were unaffected. In addition, we found that all of the normal ovarian epithelial cells and four of five ovarian cancer cell lines produce transforming growth factor-beta ribonucleic acid and protein. CONCLUSIONS These data suggest that transforming growth factor-beta may act as an autocrine growth inhibitory factor for normal ovarian epithelium in vivo. Because most of the ovarian cancer cell lines are relatively resistant to the growth inhibitory effect of transforming growth factor-beta and because one cell line does not produce transforming growth factor-beta, it is possible that loss of the transforming growth factor-beta pathway may play a role in the development of some ovarian cancers.

Epidermal growth factor receptor expression in normal and malignant endometrium

Epidermal growth factor receptor expression in fresh-frozen uterine tissues was studied with the use of monoclonal antibody 528, which recognizes an epitope on the external domain of the epidermal growth factor receptor. Immunohistochemically detectable epidermal growth factor receptor was seen in all uterine cell types in 19 of 20 normal uteri. Staining of endometrial glands and endometrial stromal cells was consistently greater than that of myometrium, and no variation in intensity or distribution of staining was seen during the menstrual cycle. Immunohistochemically detectable epidermal growth factor receptor was found less frequently in endometrial adenocarcinomas than in normal endometrium (p less than 0.01). Thirteen of 40 endometrial adenocarcinomas (32.5%) did not express detectable receptor. Epidermal growth factor receptor expression did not correlate with histologic grade, depth of myometrial invasion, estrogen-progesterone receptor status, the presence of extrauterine metastases, or the development of recurrent disease.

Preoperative evaluation of serum CA 125, TAG 72, and CA 15-3 in patients with endometrial carcinoma

We evaluated 109 women with endometrial carcinoma to determine the accuracy of preoperative tumor-associated antigen levels (CA 125, CA 72, CA 15-3) for prediction of extrauterine disease and whether TAG 72, CA 15-3, or both would improve the predictive value of CA 125 alone. Eleven (12%) of 80 patients with disease confined to the uterus or positive cytologic findings had CA 125 values greater than 35 U/ml versus 12 (65%) of 20 patients with extrauterine metastasis. Therefore CA 125 values had sensitivity of 65% and specificity of 88%. The TAG 72 level was elevated (greater than 6 U/ml) in 4% of patients with localized disease and 30% with metastasis. CA 15-3 was elevated (greater than 30 U/ml) in 17% and 65% in these categories, respectively. TAG 72 or CA 15-3 levels did not improve the combination of sensitivity and specificity of CA 125 alone. In addition, only one of 10 patients with microscopic metastasis (three cases) or positive peritoneal cytology (seven) had elevation of any of these tumor-associated antigen levels. Failure to detect occult metastasis and a high false-positive rate limit the role of these tumor-associated antigen assays in the preoperative evaluation of patients with endometrial carcinoma.

The role of tumor markers in gynecologic oncology

Human chorionic gonadotropin is a highly sensitive and specific tumor marker for gestational trophoblastic neoplasia that accurately reflects tumor volume and the clinical course of disease. In women with endodermal sinus tumors and embryonal carcinomas, alpha-fetoprotein usually is a reliable marker, and it accurately predicts the presence of yolk sac elements in mixed germ cell tumors. CA 125 is the most widely utilized tumor marker presently available for use in patients with epithelial ovarian cancer. It has utility in monitoring therapy and differentiating benign from malignant pelvic masses. Measurement of serial CA 125 levels in postmenopausal women may facilitate screening for occult early stage disease. In the future, monoclonal antibodies that recognize tumor-associated antigens may prove useful for radionuclide imaging.

Efficacy of the metastatic survey in the staging of gestational trophoblastic disease.

Between 1965 and 1987, 190 patients with nonmetastatic and 134 patients with metastatic gestational trophoblastic disease (GTD) underwent initial metastatic survey at the Southeastern Regional Trophoblastic Disease Center (Durham, NC). These patients were evaluated for characteristics which might predict the presence of high‐risk metastases before a full radiographic survey was obtained. Minimal staging evaluation of all patients included history and examination, quantitative HCG level by β‐subunit radioimmunoassay, chest radiograph, and evaluation for brain and liver metastases with radionuclide or computed tomography (CT) scans. Seventeen patients had high‐risk sites of metastases (i.e., those outside lungs, vagina, or pelvis). Characteristics were identified which might predict high‐risk metastases: (1) all had metastases in lungs or vagina; (2) 13 of 17 (76%) had at least one other high risk factor (i.e., β‐HCG titer > 40,000 mIU/ml, greater than 4 months since onset of symptoms or antecedent term pregnancy; and (3) 15 of 17 (88%) had obvious symptoms or signs related to high‐risk metastases. The authors then evaluated these criteria to identify high‐risk metastasis: (1) asymptomatic patients with GTD are screened for therapy with history and physical examination, HCG level, and chest radiograph or CT of the lungs; and (2) further radiographic imaging is used only for patients with signs or symptoms of high‐risk metastases, identifiable lung or pelvic metastases, or other high‐risk clinical factors. Using this criteria, patients with high‐risk metastases were identified with sensitivity of 100% and specificity of 63%. Approximately 60% of patients did not require further radiographic evaluation.

Preoperative evaluation of macrophage colony-stimulating factor levels in patients with endometrial cancer

OBJECTIVE Our purpose was to examine the relationship between preoperative serum levels of macrophage colony-stimulating factor, alone and in combination with CA 125, and the presence of prognostic clinicopathologic factors and subclinical metastases in women with endometrial cancer. STUDY DESIGN Ninety-two women who underwent primary exploration for endometrial adenocarcinoma had preoperative serum samples evaluated for macrophage colony-stimulating factor and CA 125 levels. Multivariate analysis was used to determine the associations of surgicopathologic findings with macrophage colony-stimulating factor and CA 125 levels. Logistic regression analysis was used to identify factors associated with the risk of extrauterine disease. The association of macrophage colony-stimulating factor and CA 125 levels with stage, grade, and depth of myometrial invasion and histologic characteristics were analyzed with Fishers two-tailed exact test. RESULTS Elevated levels of macrophage colony-stimulating factor were not associated with depth of myometrial invasion, histologic grade, or histologic cell type; however, advanced stage (p = 0.02) and the presence of lymph node metastases (p = 0.04) were associated with elevated levels. Sensitivity and specificity of macrophage colony-stimulating factor for predicting extrauterine disease were 42% and 89%, respectively. If either an elevated macrophage colony-stimulating factor or an elevated CA 125 level was used to predict extrauterine disease, the sensitivity was increased to 67% but the specificity was decreased to 78%. Macrophage colony-stimulating factor elevations predicted lymph node metastases with a sensitivity of 50% and a specificity of 86%. A multivariate regression model showed CA 125 to be the most significant predictor of extrauterine disease; macrophage colony-stimulating factor also contributed prognostic information (p = 0.02). The sensitivity and specificity of the multivariate model for predicting extrauterine disease were 75% and 73%, respectively. CONCLUSION Macrophage colony-stimulating factor and CA 125 are neither sensitive nor specific enough to be used as predictors of the presence or absence of extrauterine disease in patients with endometrial cancer.

Regulation of growth of normal ovarian epithelium and ovarian cancer cell lines by transforming growth factor-β

OBJECTIVE: The purpose of this study was to study the role of transforming growth factor-(3 in regulation of proliferation of normal and malignant ovarian epithelial cells. STUDY DESIGN: We examined production of and responsiveness to transforming growth factor-(3 in primary monolayer cultures of epithelial cells from five normal human ovaries and in five ovarian cancer cell lines. RESULTS: In normal ovarian epithelial cells, proliferation always was inhibited by transforming growth factor-(3 (>40%) (p 95%) (p < 0.01), two were only modestly inhibited (15% to 20%) (p < 0.05), and two were unaffected. In addition, we found that all of the normal ovarian epithelial cells and four of five ovarian cancer cell lines produce transforming growth factor-(3 ribonucleic acid and protein. CONCLUSIONS: These data suggest that transforming growth factor-(3 may act as an autocrine growth inhibitory factor for normal ovarian epithelium in vivo. Because most of the ovarian cancer cell lines are relatively resistant to the growth inhibitory effect of transforming growth factor-[3 and because one cell line does not produce transforming growth factor-(3, it is possible that loss of the transforming growth factor-(3 pathway may playa role in the development of some ovarian cancers. (AM J OSSTET GVNECOL 1992;166:676-84.)

Urethral obstruction after anterior colporrhaphy: Correction by simple vaginoplasty

OBJECTIVES Bladder outlet obstruction is a well-known complication of anti-stress incontinence procedures including retropubic suspensions, needle suspensions, and slings. Relief of obstruction after these procedures usually requires freeing the urethra from its superior attachments. Because the anterior colporrhaphy does not involve suspension above the urethra, obstruction can be relieved by a simple plastic procedure involving the anterior vaginal wall. METHODS We describe 2 cases in which a simple plastic procedure was used to correct urodynamically confirmed obstruction after anterior colporrhaphy. RESULTS One patient became completely asymptomatic. The other had subjective and urodynamic resolution of her obstructive symptoms, but persistent detrusor instability. CONCLUSIONS A simple plastic procedure can be used to correct urethral obstruction after anterior colporrhaphy.

Heterogeneity of antigen expression in advanced epithelial ovarian cancer

Immunohistochemical techniques were used to evaluate the expression of six antigens (CA 125, TAG 72, CA 19-9, OVTL3, DF3, and transferrin receptor) in frozen sections from the primary tumor and metastases of 20 patients with epithelial ovarian cancer. Heterogeneous expression of most antigens was observed within a given tumor nodule, but in each patient the proportion of cells expressing an antigen was similar in the primary tumor and metastases. To explore the stability of the antigenic phenotype of individual cells, we studied CA 125 expression in an ovarian cancer cell line. Cells were separated into CA 125-positive and -negative groups using fluorescence-activated cell sorting. After the two groups of cells were recultured separately, only 38% of cells originally sorted as CA 125 positive still expressed CA 125, whereas 27% of cells sorted as CA 125 negative expressed CA 125. That cells may gain or lose CA 125 expression in culture suggests that expression of CA 125 by ovarian cancer cells is not a stable trait.