Oral contraceptive use and risk of gestational trophoblastic tumors.

BACKGROUND: Gestational trophoblastic disease refers to a spectrum of rare benign and malignant gynecologic disorders whose pathogenesis is not well understood. Recent studies from China and the United States have raised the hypothesis that long-term use of oral contraceptives before conception may increase the risk of gestational trophoblastic tumors. A multicenter case-control study of gestational trophoblastic tumors was undertaken to test this hypothesis. METHODS: Telephone interviews were conducted with 235 case patients, including 50 with gestational choriocarcinoma, and 413 control subjects matched on recentness of pregnancy, age at pregnancy, and area of residence. Relative risks (odds ratios) were computed by conditional logistic regression. Reported P values are two-sided. RESULTS: The relative risk estimate for ever having used oral contraceptives before the index pregnancy was 1.9 (95% confidence interval [CI] = 1.2-3.0), and the risk increased with duration of use (P for trend = .05). The estimate was highest for women who used oral contraceptives during the cycle in which they became pregnant (relative risk = 4.0; 95% CI=1.6-10), but there was no consistent pattern according to the time interval since last use. Separate analyses of choriocarcinoma and persistent mole yielded similar results, i.e., the relative risk estimates for oral contraceptive use were 2.2 (95% CI=0.8-6.4) and 1.8 (95% CI=1.0-3.0), respectively. Control for the number of sexual partners, which was independently associated with risk (P for trend = .05), did not materially change the results. CONCLUSIONS: This study, the largest to date, indicates that long duration of oral contraceptive use before conception increases the risk of gestational trophoblastic tumors. These findings may provide clues to the pathogenesis of this rare disease. Changes in use of oral contraceptives are not warranted, however, because the incidence attributable to oral contraceptive use is very low.

PIP: Recent studies in the US and China have suggested that long-term use of oral contraceptives (OCs) before conception increases the risk of gestational trophoblastic tumors. This association was investigated further in a study conducted at 8 US medical centers that specialize in the treatment of this gynecologic disorder. 235 cases, including 50 women with gestational choriocarcinoma, were matched with 413 controls on recentness of pregnancy, age at pregnancy, and area of residence. The relative risk estimate for ever-use of OCs before the index pregnancy was 1.9 (95% confidence interval [CI], 1.2-3.0) and the risk increased with duration of OC use. The relative risk was highest (4.0; 95% CI, 1.6-10.0) for women who used OCs during the cycle in which they became pregnant, but there was no consistent pattern according to the time interval since last OC use. The relative risks for choriocarcinoma and persistent mole associated with OC use were 2.2 (95% CI, 0.8-6.4) and 1.8 (95% CI, 1.0-3.0), respectively. This study, the largest to date, suggests that a long duration of OC use before conception does, indeed, increase the risk of gestational trophoblastic tumors.

Case-control study of gestational choriocarcinoma.

A multicentered case-control study of 75 women who had had gestational choriocarcinoma was conducted to investigate the role of reproductive and fertility factors as well as other potential risk factors in the development of this disease. Control women, identified through random digit dialing, were individually matched to cases by year of pregnancy, age at pregnancy, and geographical proximity of residence. Choriocarcinoma risk was decreased significantly as body mass index increased (P for trend = 0.03). Cases reported low-calorie dieting significantly less frequently than controls [odds ratio estimate (OR) = 0.50, P = 0.05] and were significantly less likely to participate in regular exercise (OR = 0.38, P = 0.004). Compared to women with a heavy menstrual flow, those with light menstruation had significantly elevated risk (OR = 6.69, P = 0.01). Menarche after age 12 was also associated with elevated risk of this disease (OR = 2.89, P = 0.003). There were significantly more pairs of dizygotic twins born to cases and their first degree relatives than to controls (12 case families with 13 sets of twins versus 3 sets in control families, OR = 6.36, P = 0.009). Cases were more likely to have married more than once (OR = 13.0, P less than 0.001), and infrequent intercourse was a significant risk factor (OR for weekly or less often was 3.00, P = 0.04). Risk estimates for postmolar choriocarcinoma were not significantly different from those for all other cases. These observations and some descriptive features of the disease suggest that hormonal factors, specifically below normal estrogen levels, may be associated with a disruption of normal ovulation and thus predispose to choriocarcinoma.

Pharmacokinetic and phase I trial of intraperitoneal carboplatin and cyclosporine in refractory ovarian cancer patients.

PURPOSE: The feasibility and pharmacokinetics of cyclosporine (CsA) delivered intraperitoneally (IP) have not been previously explored. We performed a pharmacokinetic study of IP CsA followed by a phase I dose-escalation trial of the combination of IP CsA and carboplatin in refractory ovarian cancer patients. PATIENTS AND METHODS: A pilot study was performed of three patients who received 1, 10, and 20 mg/kg IP CsA alone. Subsequently, a phase I trial of 35 patients was performed between April 1990 and April 1993. Whole-blood and IP fluid CsA concentrations were measured at serial time points. The highest dose delivered IP was 34.6 mg CsA/kg in combination with carboplatin (250 mg/m2 or 300 mg/m2, depending on creatinine clearance), which was not dose-escalated. The area under the concentration-time curve (AUC) for CsA and half-life (T1/2) were calculated. Objective and serologic responses were noted, and toxicity was graded using the National Cancer Institute common toxicity criteria. RESULTS: The feasibility of delivering IP CsA alone was established. We observed a 1,000:1 ratio between IP fluid and blood concentrations at 20 mg CsA/kg. Pharmacokinetic analysis confirmed that at 20 mg CsA/kg, there was an IP fluid-to-blood AUC ratio of 600:1 in favor of peritoneal exposure. At the highest dose delivered, 34.6 mg CsA/kg, the mean IP CsA levels of 1,110 micrograms/ mL were tolerated moderately well and the IP fluid-to-blood ratio of 1,000:1 was maintained. Blood and IP CsA concentrations were analyzed in the presence and absence of IP carboplatin. At 20 mg CsA/kg, there was no difference in either mean blood CsA levels (0.9 microgram/ mL) or mean IP CsA concentrations (1,000 micrograms/mL) obtained in the absence or presence of carboplatin. The most common toxicity in the phase I study was anemia, seen in 66% of patients. Common toxicities at the maximum CsA dose delivered (34.6 mg/kg) were anemia, leukopenia, thrombocytopenia, and hypertension. In this trial, three objective responses (two complete and one partial) were observed for a duration of 3 to 11 months. Control of platinum-resistant ascites was an important feature, noted in five of eight patients. CONCLUSION: We have established the feasibility of delivering IP CsA up to doses of 34.6 mg/kg in conjunction with carboplatin, and the sustaining of IP fluid to blood ratios of 1,000:1. The IP administration of CsA resulted in a favorable ratio of exposure for the peritoneal cavity compared with systemic exposure, indicating a therapeutic advantage of this approach with a significant decrease in systemic toxicity. We recommend that 34.6 mg/ kg of IP CsA be tested as a phase II dose in combination with carboplatin in refractory ovarian cancer patients. This report provides the groundwork for future studies using IP CsA, both as a chemomodulator of platinum and of multidrug resistance.

Modulation of platinum sensitivity and resistance by cyclosporin A in refractory ovarian and fallopian tube cancer patients: a phase II study.

Our objective was to assess the activity of cyclosporin A (CsA) used as a chemomodulator of carboplatin in refractory ovarian and fallopian tube cancer patients. Fifty-one patients (47 epithelial ovarian, 1 ovarian mixed mesodermal tumor, and 3 fallopian tube carcinomas) were enrolled in a prospective Phase II trial of CsA and carboplatin. CsA was infused as a loading dose of 10 mg/kg over 5 h, followed by carboplatin infused over 30 min at an AUC of 6 mg/ml x min, then a 24-h continuous infusion of 11.6 mg/kg CsA. The patients received this protocol as second- to sixth-line therapy and had received between 1 and 3 prior platinum-based regimens. Eight patients received more than six cycles every 28 days, 34 patients received three to six cycles; and 9 patients received only one or two cycles. Thirty-eight patients were evaluable for objective response, and in an additional nine patients, CA-125 was the only marker of response. Four patients had no marker of disease. Of evaluable patients, 74% were platinum resistant. There were nine objective responses (one complete and eight partial responses) for an overall response rate in evaluable patients of 24%, with a median duration of response of 7 months (range, 3-38+ months). No responses were seen in patients who had received only one or two cycles of therapy. Among the strictly defined platinum-resistant patients, there was an overall 14% response rate, including one partial response seen after five prior regimens of chemotherapy including paclitaxel, and one ongoing complete response for 38+ months. Among the rest of the patients (those who were potentially platinum sensitive), there was an overall 50+ response rate; four of five responses were seen in patients with a platinum-free interval of <24 months, with only one response seen in a patient with a platinum-free interval of >24 months. Of evaluable patients, 34% had stable disease for a duration of 3-19 months. The most common grade 3 or 4 toxicity, thrombocytopenia, was seen in 22% of the patients. Hypertension, which responded to medications, was seen in 18% of the patients during the CsA infusion. We concluded that this CsA/carboplatin regimen is active in potentially platinum-sensitive patients and compares well with the expected response rate of 30% in patients with a platinum-free interval <24 months who are retreated with platinum. Moreover, this regimen had modest but real activity in platinum-resistant patients.

Fallopian tube carcinoma.

Twenty-one patients with fallopian tube carcinoma from Yale-New Haven Medical Center are reviewed. Most patients who died of disease did so in the first two years after diagnosis, even following complete resection, clearly indicating the need for adjuvant therapy. Negative second-look surgery did not provide assurance of permanent remission. There was a high recurrence rate with Stage I and completely resected Stage II and III disease (8 of 14 patients). Some recurrences occurred late, up to nine years after initial diagnosis. We recommend whole abdomino-pelvic radiation if no disease greater than 2 cm3 bulk exists after surgery. Chemotherapy may be an alternative to radiation as primary adjuvant treatment in early stage disease. Chemotherapy for unresectable disease or recurrent disease has shown palliation with occasional prolonged survival but no patient with recurrent disease survived longer than two years.

Pretreatment prognostic factors in carcinoma of the uterine cervix: a multivariable analysis of the effect of age, stage, histology and blood counts on survival.

From January, 1953 through December, 1977, 910 previously untreated patients with invasive carcinoma of the uterine cervix (Stages IB-IVB) were seen at Yale-New Haven Medical Center and affiliated hospitals. An extensive retrospective analysis was undertaken in an attempt to identify prognostically significant pretreatment factors. The patients studied were uniformly staged according to the current FIGO recommendations and the majority of patients had been treated under standardized protocols combining external beam radiation therapy and intracavitary radium. Pretreatment parameters, including prior medical illnesses, gross tumor characteristics, histology, and blood parameters were studied, employing stepwise Cox regression analyses to identify the possible effects of all factors and all two-way interactions among factors on survival, disease-free survival and freedom from local-regional failure, controlling for stage of disease. FIGO stage, patient age at diagnosis, pretreatment neutrophil count and hematocrit, uterine position, prior subtotal hysterectomy, histology, history of diabetes mellitus and number of pregnancies were all found to have prognostic significance. When other factors including stage of disease were controlled for, increased tumor size was associated with decrease disease-free survival and local-regional control rates.

High level expression of fms proto-oncogene mRNA is observed in clinically aggressive human endometrial adenocarcinomas.

Six micron paraffin sections of paraformaldehyde-fixed endometrial currettings of 21 benign and neoplastic endometrial specimens were assayed for tumor cell-specific oncogene expression by in situ hybridization with probes for six oncogenes, beta-actin, and the E. coli plasmid pBR322. In the benign hyperplasias and invasive adenocarcinomas, multiple oncogenes, including erbB, fms, c-myc, and Ki-ras were expressed at significant levels. For the adenocarcinomas, statistical analysis demonstrated that high levels of expression of fms-complementary mRNA correlated strongly with clinicopathologic features (high FIGO histologic grade, high FIGO clinical stage, deep myometrial penetration) predictive of aggressive clinical behavior and poor outcome. The authors discuss the role which M-CSF receptor (the fms gene product) and locally-produced M-CSF may play in the development of the observed aggressively-malignant phenotypes. They also propose that pre-hysterectomy assay of fms gene expression in endometrial currettings in FIGO Stage I patients might be clinically useful to help identify preoperatively those patients with deep myometrial penetration or other locoregional spread.

Circulating levels of CSF-1 (M-CSF) a lymphohematopoietic cytokine may be a useful marker of disease status in patients with malignant ovarian neoplasms.

We have previously reported our observations of epithelial tumor cell expression of transcripts and protein antigens of CSF-1 and transcripts of a protein closely related--if not identical--to the CSF-1 receptor in ovarian and endometrial neoplasms in vivo and in vitro. In the present communication, we extend these investigations to analyze the clinical utility of determinations of plasma CSF-1 concentrations in 125 samples from 33 patients with ovarian neoplasms and one patient with benign endometriosis. We observed that plasma CSF-1 levels in patients with active and recurrent neoplastic disease were markedly elevated and follow changes in disease status in individual patients. These and other results presented in this communication suggest that not only could CSF-1 be a useful circulating tumor marker in ovarian carcinoma patients, but also that in combination with measurements of other markers--such as CA-125--determinations of plasma CSF-1 levels might actually improve the accuracy of "tumor marker"-based assessments of disease status in patients with malignant ovarian neoplasms.

Effective treatment of stage I uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (192Ir) and chemotherapy.

PURPOSE: Uterine papillary serous carcinoma (UPSC) is a morphologically distinct variant of endometrial carcinoma that is associated with a poor prognosis, high recurrence rate, frequent clinical understaging, and poor response to salvage treatment. We retrospectively analyzed local control, actuarial overall survival (OS), actuarial disease-free survival (DFS), salvage rate, and complications for patients with Federation International of Gynecology and Obstetrics (FIGO) (1988) Stage I UPSC. METHODS AND MATERIALS: This retrospective analysis describes 38 patients with FIGO Stage I UPSC who were treated with the combinations of radiation therapy, chemotherapy, total abdominal hysterectomy, and bilateral salpingo-oophorectomy (TAH/BSO), with or without a surgical staging procedure. Twenty of 38 patients were treated with a combination of low dose-rate (LDR) uterine/vaginal brachytherapy using 226Ra or 137Cs and conventional whole-abdomen radiation therapy (WART) or whole-pelvic radiation therapy (WPRT). Of 20 patients (10%) in this treatment group, 2 received cisplatin chemotherapy. Eighteen patients were treated with high dose-rate (HDR) vaginal apex brachytherapy using 192Ir with an afterloading device and cisplatin, doxorubicin, and cyclophosphamide (CAP) chemotherapy (5 of 18 patients). Only 6 of 20 UPSC patients treated with combination LDR uterine/vaginal brachytherapy and conventional external beam radiotherapy underwent complete surgical staging, consisting of TAH/BSO, pelvic/para-aortic lymph node sampling, omentectomy, and peritoneal fluid analysis, compared to 15 of 18 patients treated with HDR vaginal apex brachytherapy. RESULTS: The 5-year actuarial OS for patients with complete surgical staging and adjuvant radiation/chemotherapy treatment was 100% vs. 61% for patients without complete staging (p = 0.002). The 5-year actuarial OS for all Stage I UPSC patients treated with postoperative HDR vaginal apex brachytherapy and systemic chemotherapy was 94% (18 patients). The 5-year actuarial OS for Stage I UPSC patients treated with HDR vaginal apex brachytherapy and chemotherapy who underwent complete surgical staging was 100% (15 patients). The 5-year actuarial OS for the 20 Stage I UPSC patients treated with combinations of pre- and postoperative LDR brachytherapy and postop WART was 65%. None of the 6 surgically staged UPSC patients treated with LDR radiation and WART/WPRT developed recurrent disease. For patients with FIGO Stage IA, IB, and IC UPSC who underwent complete surgical staging, the 5-year actuarial DFS by depth of myometrial invasion was 100, 71, and 40%, respectively (p = 0.006). The overall salvage rate for local and distant recurrence was 0%. Complications following HDR vaginal apex brachytherapy included only Radiation Therapy Oncology Group (RTOG) grade 1 and 2 toxicity in 16% of patients. However, complications from patients treated with WART/WPRT, and/or LDR brachytherapy, included RTOG grade 3 and 4 toxicity in 15% of patients. CONCLUSION: Patients with UPSC should undergo complete surgical staging, and completely surgically staged FIGO Stage I UPSC patients can be effectively and safely treated with HDR vaginal apex brachytherapy and chemotherapy. Both OS and DFS of patients with UPSC are dependent on depth of myometrial invasion. The salvage rate for both local and distant UPSC recurrences is extremely poor. Complications from HDR vaginal apex brachytherapy were minimal.

Theca lutein ovarian cyst may be pathognomonic for trophoblastic neoplasia.

Two cases are presented in which theca lutein tissue was found at the time of indicated pelvic surgery performed long after treatment for hydatidiform mole. This indicator for the presence of trophoblastic tissue was not recognized, and clinical metastatic gestational trophoblastic neoplasia subsequently developed in each patient. Theca lutein tissue found at pelvic surgery merits investigation by beta-human chorionic gonadotropin radioimmunoassay and is likely to be associated with subclinical latent trophoblastic neoplasia.

Hydatidiform mole and gestational trophoblastic disease in Southern Connecticut.

Of 127 patients with hydatidiform mole in southern Connecticut, 34 (28%) received chemotherapy for persistently elevated human chorionic gonadotropin (hCG) titers. An hCG regression curve was found to be useful if not mandatory for following patients. Excess uterine size, theca lutein cysts, uterine bleeding, and histologic trophoblastic hyperplasia were relative discriminators of the need for chemotherapy. In the absence of metastases, an hCG titer was the only valid discriminator for initiating chemotherapy, provided the patient could be followed consistently and reliably. The indications for initiating chemotherapy are discussed. Early diagnosis and close follow-up were associated with low morbidity. Five of 6 patients with metastatic disease were referred from outside the center.

Cell-mediated immunity and blocking factor in ovarian carcinoma.

Lymphocyte-mediated cytotoxicity (cell-mediated immunity) to ovarian carcinoma cells and serum blocking factor were measured in 37 patients. Short-term cultures of tumor cells and a low ratio of effector to target cells were used throughout the study, minimizing nonspecific cytotoxicity. Sixteen patients were followed for long periods of time, and correlation with the course of the disease and with therapy could be obtained. Although the level of cell-mediated immunity did not always correspond to the clinical status of the patient, the presence of blocking factor was associated with clinical relapse in 14 of 16 patients. Chemotherapy with single alkylating agents or combinations of drugs caused no significant or permanent depression of cell-mediated immunity as measured in this way. In addition, blocking factor disappeared in 2 patients during remission. It appears that the chemotherapy for ovarian carcinoma may not be significantly immunosuppressive against established levels of cell-mediated immunity and may in certain instances have effects potentially beneficial to the host as evaluated by lymphocyte-mediated cytotoxicity and blocking factor studies.

Vulvar pain and dyspareunia due to glomus tumor.

Reported is a patient with long standing vulvar pain and severe introital dyspareunia whose symptoms were cured by removal of a glomus tumor of the vulva.

Ultrasound cystourethrography by perineal scanning for the assessment of female stress urinary incontinence.

Perineal scanning using linear array ultrasound was used as an alternative to radiologic cystourethrography in the investigation of female urinary incontinence. The technique provides similar information to that obtained by fluoroscopy without exposing the patient and the physician to radiation. The bladder neck and urethra as well as the urodynamic catheter are readily visualized. Familiarity with the unusual configuration of the sonogram needs to be attained.

Stress Urinary Incontinence.

Stress urinary incontinence (SUI) was studied in 125 women who were subjected to simultaneous urodynamic and radiologic evaluation. This included cystometry, urethral pressure profiles, measurement of effective urethral length, estimation of urethral mobility, and alterations in the urethrovesical angles during stress. The most common abnormality was a hypermobility of the proximal urethra with loss of its intraabdominal position during stress, associated with changes in the urethrovesical angle. Fixation of the posterior urethra, loss of effective urethral length, low resting urethral pressure, and true neurovesical dysfunction were also found in some of the patients. Uninhibited bladder contractions were found in 22% of cases, but in most instances they were the result of SUI and ceased after surgical repair.

Evaluation of the role of second-look surgery in ovarian cancer.

The role of second-look surgery in the management of patients with ovarian cancer has come under question. One hundred one patients have undergone the operation at Yale University over the last decade. Of 67 who had epithelial ovarian cancer, 43% had positive and 57% had negative second-look surgery. Multivariate analysis revealed that stage was a significant prognostic factor with regard to second-look surgery findings, as well as absolute and disease-free survival. We found initial tumor size and results of cytology at second-look surgery to be prognostic factors with regard to survival after a positive second-look surgery. Survival after negative second-look surgery was significantly greater than that after a positive operation. However, no improvement in survival accrued to the group of advanced-stage, platinum-treated patients who underwent second-look surgery, compared with a similar group of patients who were eligible but did not undergo the procedure. We conclude that second-look surgery in epithelial ovarian cancer patients should be limited to experimental protocol situations in which precise measurement of tumor size may be important. In ovarian germ cell malignancies, second-look surgery, in the absence of tumor markers, can be justified.

Psychosocial reactions to the diagnosis of gynecologic cancer.

Data are presented on the psychosocial impact of gynecologic cancer derived from both a structured interview and self-report scales administered to 60 women newly diagnosed with cervical, uterine, and ovarian malignancies. Findings show that such women experience mild to moderate symptoms of depression and anxiety, as well as impairment of vocational, domestic, and sexual functioning. The women with cancer reported significantly fewer symptoms of depression and social impairment than acutely depressed women without cancer. The women studied also demonstrated significantly more symptoms of depression and social impairment than women without psychiatric disease from randomly selected community samples. The symptoms of depression experienced by women with ovarian cancer, women receiving triple-agent chemotherapy and women with poorly differentiated tumors of the endometrium and ovary approached the level of acute symptoms typically reported by women entering outpatient psychiatric clinics. These observations should enhance the understanding of these problems among gynecologists and other health care providers in offering appropriate psychosocial support for women with gynecologic cancer.

Uterine papillary serous carcinoma.

Reviewed are 37 patients with the diagnosis of uterine papillary serous carcinoma. Clinically, 19 patients presented as stage I, 9 as stage II, 1 as stage III, and 8 as stage IV. Four of 18 patients with clinical stage I disease who underwent surgery had pelvic metastases and five had disease spread beyond the pelvis. Three of nine clinical stage II patients had intraabdominal metastases. At least 50% myometrial invasion was found in 43% of the 30 hysterectomy specimens, and lymphatic invasion in the myometrium was demonstrated in 78% of the specimens. Each of the 15 patients with surgical stage I or II disease received local radiation therapy: 10 are alive and of these 9 are disease-free. Each of nine clinical stage II patients received intense radiation therapy and hysterectomy; seven are alive and of these four are disease free. The five-year survival for combined surgical stages I and II patients was 45%. The three-year survival for combined surgical stages III and IV was 11%. Thirteen patients have been treated with combination chemotherapy, 11 with cis-platinum-based combinations. Nine of these patients are dead; four are alive, with three of these having progressive disease.

Are cytosol estrogen and progestin receptors of prognostic significance in the management of epithelial ovarian cancers?

Cystosol estrogen and progestin receptor levels in tumor samples from 101 patients with previously untreated primary epithelial ovarian cancers were correlated with patient survival. Patients with stage I and II disease whose tumors contained elevated levels of cytosol progestin receptors had an improved survival over patients with tumors containing low levels of cytosol progestin receptors. However, patients with advanced ovarian cancers and low cytosol progestin receptors had significantly longer survival. The four-year estimated duration of survival with advanced disease and cytosol progestin receptors less than seven was 82%, whereas if the cytosol progestin receptors were seven or more, the four-year estimated duration of survival was only 10%. The explanation for this dichotomy is not evident at this time. In this study cytosol estrogen receptor levels were not associated with survival. These results suggest that measurement of cytosol progestin receptors is of prognostic value in advanced epithelial ovarian cancers.

Pulmonary embolization of trophoblastic tissue in molar pregnancy.

A case of pulmonary embolization of trophoblastic tissue is described. The signs and symptoms of this syndrome are discussed, and its optimal management is outlined.