BRCA1 germline mutations and polymorphisms in a clinic-based series of ovarian cancer cases: a Gynecologic Oncology Group study.

OBJECTIVE: The aims of this study were to determine the frequency of BRCA1 gene alterations in an unselected, clinic-based series of ovarian cancer cases; to evaluate the usefulness of family history in predicting the likelihood of a disease-causing mutation; and to document the occurrence of polymorphic variants in BRCA1 and to determine their distribution among families accordingly to history of breast and/or ovarian cancer. METHOD: Two hundred fifty-eight women with primary epithelial ovarian cancer, entered onto a nonclinical protocol of the Gynecologic Oncology Group, were analyzed for BRCA1 germline alterations by single-strand conformation polymorphism analysis. RESULTS: Protein-truncating mutations in BRCA1 were identified in 12 patients (4.6%). The median age of cancer diagnosis in BRCA1 mutation carriers was 47 years compared to 57 years in patients without mutations (P = 0.02). All but 1 of the patients with BRCA1 mutations reported a family history of breast and/or ovarian cancer and 8 had a first-degree relative with cancer. Twelve mutations of unknown significance were also identified. An association was also noted between the presence of common polymorphisms in BRCA1 and family history of cancer. Polymorphisms were present at higher frequency among women without a family history of cancer compared to women with positive family histories, suggesting they are associated with reduced risk. CONCLUSION: In a clinic-based series of ovarian cancer patients, germline BRCA1 mutations were detected in 12 of 258 (4.6%) patients. A strong correlation was noted between the presence of mutations and family history of breast and/or ovarian cancer, indicating that these women are most likely to benefit from genetic susceptibility testing.

Paclitaxel in the treatment of carcinosarcoma of the uterus: a gynecologic oncology group study.

OBJECTIVE: The goal of this study was to estimate the clinical activity of paclitaxel in patients with persistent or recurrent carcinosarcoma of the uterus who have failed other treatments. METHODS: The Gynecologic Oncology Group (GOG) conducted a phase II study of paclitaxel 170 mg/m(2) (135 mg/m(2) in those with prior irradiation) intravenously every 3 weeks in patients with histologic confirmation of carcinoma and measurable disease who had failed appropriate local therapy. RESULTS: A total of 53 patients were entered into the study between September 1994 and January 1997; 44 patients were evaluable for response. The median age of the patients treated was 65 years (range: 38-79). Twenty-six patients had heterologous mixed mesodermal tumors (MMTs) and 18 patients had homologous tumors. A median of three courses were administered (range: 1-18). Fifteen patients had previous radiation therapy and 33 patients had failed prior chemotherapy. Eight patients (18.2%) had a response to paclitaxel: four patients had a complete response and four had a partial response. Neutropenia was the most common toxic effect. CONCLUSIONS: Paclitaxel had moderate activity in patients with carcinosarcoma of the uterus. The GOG is currently studying the combination of paclitaxel and ifosfamide versus ifosfamide alone for patients with advanced or recurrent carcinosarcoma of the uterus.

Simultaneously detected endometrial and ovarian carcinomas--a prospective clinicopathologic study of 74 cases: a gynecologic oncology group study.

OBJECTIVES: The coexistence of carcinomas of the endometrium and ovary occurs in about 10% of women with ovarian carcinoma. It is often unclear whether this represents synchronous primary tumors or metastasis from endometrium to ovary, or from ovary to endometrium; consequently, staging, therapy, and expected outcome are uncertain. The Gynecologic Oncology Group sought to study patients with simultaneously detected adenocarcinomas in the endometrium and ovary with disease grossly confined to the pelvis to explore the possible correlation among discrete tumor subsets, natural history, and survival. METHODS: Between 1985 and 1991, 85 patients were prospectively enrolled, of whom 74 were eligible. All were initially treated with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and staging laparotomy, with radiation and chemotherapy left to the discretion of the treating physician and patient. Fifteen pathologic variables were examined to identify differences in tumor behavior. RESULTS: Of the 74 patients, 23 (31%) had microscopic spread of tumor in the pelvis or abdomen. Sixty-four (86%) patients had endometrioid carcinomas in both the endometrium and the ovary, and endometriosis was found in the ovary of 23 (31%) patients. There was concordance between the histologic grade of the tumor in the ovary and the uterus in 51 (69%) patients. The estimated probability of recurrence 5 years following staging surgery is 15.1% (95% confidence interval (CI): 8.7-25.2%). The presence of metastasis discriminated two groups of patients that experienced different probabilities of recurrence within 5 years: 10.0% (95% CI: 4.32-21.3%) for those with tumors confined to the uterus and ovary and 27.1% (95% CI: 13.0-48.5%) for those with metastasis (hazard ratio = 4.6, P = 0.006). The histologic grades of ovarian and uterine tumors also distinguished groups of patients with different probabilities of recurrence at 5 years: 8.0% (95% CI: 2.8-21.3%) for those patients with no more than grade 1 disease at either site and 22.4% (95% CI: 11.8-38.4%) for those with a higher grade in either the ovary or the endometrium (hazard ratio = 3.1, P = 0.047). The estimated overall probability of surviving 5 years is 85.9% and that of surviving 10 years is 80.3%. CONCLUSION: The prognosis for women with simultaneously detected carcinomas in the uterus and ovary with gross disease confined to the pelvis is surprisingly good, particularly for those with disease microscopically limited to the uterus and ovary or of low histologic grade.

Postmenopausal virilization, simple ovarian cyst, and hilus cell hyperplasia--is there an association?

OBJECTIVE: To report a case of virilizing ovarian hilus cell hyperplasia detected postmenopausally in association with a simple cyst and to review the related literature, including four similar cases. METHODS: Hormonal and pathologic studies were conducted, and ovarian venous catheterization was performed during total abdominal hysterectomy. RESULTS: In our 69-year-old female patient, serum testosterone levels were 508, >3,200, and 11 ng/dL, respectively, in peripheral blood preoperatively, in ovarian venous blood obtained intraoperatively, and in peripheral blood postoperatively. The wall of the cyst contained several clusters of hilus cells, which were also found asymmetrically lateralized to the affected ovary. CONCLUSION: Hilus cell hyperplasia should be suspected in any case of postmenopausal virilization in which ultrasonography or magnetic resonance imaging suggests the presence of a simple ovarian cyst.

Lack of efficacy of 24-h infusional topotecan in platinum-refractory ovarian cancer: A Gynecologic Oncology Group trial.

BACKGROUND: The aim of this study was to evaluate the efficacy of a more convenient topotecan administration schedule in the second-line treatment of advanced platinum-refractory ovarian cancer. METHODS AND MATERIALS: The Gynecologic Oncology Group conducted a Phase II trial of 24-h infusional topotecan (8.5 mg/m(2)), repeated every 3 weeks in 26 patients with platinum-refractory ovarian cancer (failure to respond to initial platinum-based treatment or development of recurrent disease within 6 months of completion of chemotherapy). RESULTS: Grade 4 neutropenia (85% of patients) and thrombocytopenia (12%) were the major toxicities encountered. Of the 25 patients evaluable for response, only a single patient experienced an objective response (4%). CONCLUSIONS: When employed at this dose and schedule (24-h infusion every 3 weeks), topotecan has minimal second-line activity in platinum-refractory ovarian cancer.

Intraperitoneal interferon-alpha in residual ovarian carcinoma: a phase II gynecologic oncology group study.

OBJECTIVE: The purpose of this study was to confirm the activity of interferon-alpha intraperitoneally in minimal residual epithelial ovarian cancer in a Phase II multi-institutional trial and to investigate the activity of the agent based on prior response to first-line platinum compounds. METHODS: Ninety-two patients with minimal residual (<0.5 cm) epithelial ovarian cancer at reassessment laparotomy were entered into a multicenter trial of intraperitoneal interferon-alpha given for 12 cycles unless disease progression or unacceptable toxicity occurred first. Patients were considered favorable if they were platinum sensitive and/or relapsed 6 months or longer after completing treatment and unfavorable if they were platinum insensitive and/or relapsed shorter than 6 months after completing treatment and/or had stable or progressive disease during initial therapy. A third-look laparotomy was performed within 12 weeks of completion of treatment in those patients who were in clinical remission. RESULTS: Eighty patients were clinically evaluable for toxicity only (48 favorable, 32 unfavorable) and 46 of them were evaluable for response, of whom 25 were favorable (platinum sensitive) and 21 unfavorable (platinum resistant). In the favorable group, there was a 28% surgically documented response rate (7/25 patients): 16% (4/25) had complete responses (negative reassessment operation), 12% (3/25) had partial responses, 32% (8/25) were nonresponders, and 40% (10 patients) developed progressive disease before planned reassessment operation. In the unfavorable group, there were no responding patients: 6 were nonresponders at reassessment operation and 15 developed progressive disease before planned reassessment operation. Of the 80 patients evaluable for toxicity, the most common adverse effects that were more than grade 2 were gastrointestinal (12; 15%), fever (8; 10%), neutropenia (7;9%), and leukopenia (6; 8%). Grade 4 toxicity was seen in 5 patients; each had fever and gastrointestinal toxicity, and 1 each had neutropenia and thrombocytopenia. CONCLUSIONS: Interferon-alpha is an active and generally well-tolerated agent in favorable patients with minimal residual epithelial ovarian cancer at second-look surgery. These results are comparable to those achieved with cytotoxic chemotherapy. If Phase III trials are considered in the patients with minimal residual ovarian cancer, they should be limited to the platinum-sensitive patient population.

Significance of true surgical pathologic staging: a Gynecologic Oncology Group Study.

OBJECTIVE: The object of the study was to determine the true surgical pathologic disease extent in patients with clinical stage II adenocarcinoma of the endometrium. STUDY DESIGN: As part of a Gynecologic Oncology Group surgical pathologic protocol of patients with adenocarcinoma of the endometrium, patients with clinical stage II cancers were evaluated. Among >1000 patients with early stage disease entered into this protocol group study, 148 were in clinical stage II. All patients underwent abdominal hysterectomy, bilateral salpingo-oophorectomy, and selective pelvic and para-aortic lymphadenectomy as the primary therapy. Surgical pathologic material was evaluated to determine true extent of disease. RESULTS: Only 66 of 148 (45%) of patients in clinical stage II had cancer in the cervix. Fifty-seven patients had disease limited to the upper fundus and 25 had disease extending into the lower uterine segment but not into the cervix. Among the 66 patients with disease in the cervix, only 35 had disease limited to the uterus whereas 31 patients had extrauterine disease (lymph nodes, adnexa, etc). Thus among 148 patients with diagnoses of clinical stage II disease only 35 (24%) in fact had true surgical stage II cancer. CONCLUSION: Clinical diagnosis of stage II adenocarcinoma of the uterus is a poor reflection of true surgical stage II cancer. Only when true extent of disease is known can optimally definitive therapy be determined.

All-trans-retinoic acid inhibits the proliferation of cell lines derived from human cervical neoplasia.

The purpose of this study was to determine whether all-trans-retinoic acid (RA) can inhibit the growth of cervical neoplastic cells by inducing differentiation or by increasing the secretion of transforming growth factor-beta (TGF-beta). Normal and HPV DNA-positive cervical cells (2 cell lines derived from cervical intraepithelial neoplasia (CIN), 2 HPV DNA-transfected cell lines, and 6 cervical carcinoma cell lines) were treated with RA (1 to 1000 nM), and both total viable cell count and [3H]thymidine incorporation were used to evaluate proliferation. In vitro differentiation was evaluated in organotypic (collagen gel raft) cultures with hematoxylin/eosin staining, and using specific immunostaining for fillagrin and cytokeratin 10. TGF-beta 1 and TGF-beta 2 secretion were measured with specific SELISAs. One-way analysis of variance and t tests were performed. RA causes a dose-dependent (P<0.05) growth arrest of comparable magnitude in normal ectocervical cells, in HPV DNA-transfected cell lines, in CIN-derived cell lines, and in four of six carcinoma cell lines. Endocervical cells and two carcinoma cell lines are unaffected. In vitro differentiation is decreased in CIN cells and is unchanged in carcinomas treated with RA as compared to control. Secretion of either TGF-beta 1 or TGF-beta 2 is significantly increased (P<0.05) in response to RA, both in RA-sensitive and in RA-resistant cells. RA induces growth inhibition in cervical neoplastic cell lines, including cervical carcinoma cells. This does not appear to be the result of increased differentiation or of increased TGF-beta secretion.

A bleomycin/ifosfamide/cisplatin regimen exhibits poor activity against persistent or recurrent squamous gynecologic cancers.

Persistent or recurrent squamous malignancies of the female genital tract are usually incurable by conventional therapy, and results of single agent chemotherapy have been disappointing. We undertook this study to confirm a previously reported response rate of 69%, using a regimen of bleomycin 30U, ifosfamide 5g/m2 with mesna 6g/m2, and cisplatin 50 mg/m2 (BIP) for recurrent cervical cancer. This regimen was used to treat persistent or recurrent squamous cancers in women with cervical cancer (n = 11), vaginal cancer (n = 1) and vulvar cancer (n = 1). Results were reviewed retrospectively and toxicities graded according to the criteria of the Gynecologic Oncology Group. No complete responses were seen. One patient had a partial response (10%, 95% confidence interval 0-28%). Five patients (50%), exhibiting stable disease during therapy with BIP, progressed after cessation of therapy. Of 9 women with symptoms after one cycle. Significant toxicities included neutropenic fever (3 grade 3, 3 grade 4), emesis (1 grade 3), confusion (2 grade 4), vaginal bleeding (2 grade 3), and renal failure (1 grade 3). Eight patients were transfused with a total of 28 units of red cells. After 23 months of follow-up, all patients were dead of disease. Mean survival was 10 months. Toxicity associated with this regimen can be significant, and results appear no better than those reported with single agent therapy.

Prognostic indicators of survival in advanced endometrial cancer.

Advanced endometrial cancer represents 14% of all stages but 54% of all deaths attributed to endometrial cancer. From 1973 to 1990, the charts of 137 patients with endometrial cancer (Stage III and IV) treated by the section of Gynecologic Oncology at Rush Medical College were retrospectively reviewed. The log rank method was used for univariate analysis and Cox proportional hazards regression was used for multivariate analysis. The patients were stratified as follows: Stage III, 92 (67.2%), Stage IV, 45 (32.8%); Grade 1, 15 (10.9%), Grade 2, 47 (34.3%), Grade 3, 67 (48.9%); adenocarcinoma, 93 (67.9%), adenosquamous, 18 (13.1%), adenoacanthoma, 2 (1.5%), clear cell, 1 (0.7%), papillary serous, 23 (16.8%). Using univariate analysis, median survival was 1.71 years for Stage III versus 0.68 years for Stage IV. Median survival based on treatment was as follows: radiotherapy (RT) only (n = 16), 0.89 years, surgery only (n = 36), 0.75 years, preoperative RT+surgery (n = 7), 2.5 years, surgery+postoperative RT (n = 56), 2.63 years, and other treatments (hormonal only n = 12, chemotherapy only n = 1, and no treatment n = 9), 0.6 years. Patients with vaginal extension survived a median of 0.82 years, versus 2.49 years without this factor (P = 0.002). Patients with clinically apparent parametrial involvement survived a median of 0.70 years versus 2.65 years without this factor (P = 0.0003). Multivariate analysis was possible via a surgical database (n = 99). Age > 60 (P = 0.01), parametrial involvement (P = 0.04), and abdominal metastases (P = 0.003) were significant prognostic indicators. Papillary or clear cell histology, advanced grade, and mode of treatment were not significant. Patients with abdominal metastases or parametrial extension of tumor have a significant decrease in mean survival.

Isolated vaginal recurrences of endometrial carcinoma.

PURPOSE: The authors undertook this study to evaluate the results of radiation therapy (RT) for vaginal recurrence in early stage endometrial carcinoma. MATERIALS AND METHODS: Between 1964 and 1987, 34 patients with isolated vaginal recurrences of endometrial carcinoma were treated with RT. The records were reviewed for outcome and prognostic factors, such as location of tumor recurrence, time to recurrence, size of tumor at recurrence, tumor differentiation, and total radiation dose delivered at RT. RESULTS: With a median follow-up of 48 months, the 5-year actuarial survival and disease-free survival rates were 68% +/- 4 and 60% +/- 3, respectively. Results were statistically significant for some prognostic factors, including time to tumor recurrence and total radiation dose delivered at RT to the recurring tumor. CONCLUSION: Long-term survival can be obtained for patients with an isolated vaginal recurrence of endometrial cancer treated with aggressive local-regional radiation therapy.

5-fluorouracil and low-dose leucovorin in the treatment of recurrent epithelial ovarian carcinoma. A phase II trial of the Gynecologic Oncology Group.

Twenty-one patients with recurrent epithelial ovarian carcinoma not amenable to cure with further surgery or radiotherapy were entered into a Phase II trial utilizing i.v. leucovorin at 20 mg/m2 followed by i.v. 5-fluorouracil at 425 mg/m2 administered daily for 5 days every 4 weeks for the first two courses and then every 5 weeks. Twenty-one patients were entered. Of these, 20 were eligible for toxicity assessment and 19 for response. Five had received prior radiotherapy, and all had received prior cisplatin-based chemotherapy. There was one patient response (5.3%; 95% confidence intervals for response of 0% to 26%). Toxicity was moderate with 5 of 20 (25%) grade 3 or 4 leukopenia, 12 of 20 (60%) grade 3 or 4 granulocytopenia, 1 of 20 (5%) grade 3 thrombocytopenia, 5 of 20 (25%) grade 3 GI toxicity, and 2 of 20 (10%) grade 3 neurotoxicity. There was one toxic death in a patient who developed granulocytopenia and pneumonia after her third course of treatment. This dose schedule of 5-fluorouracil and leucovorin has minimal activity in patients with recurrent epithelial ovarian carcinoma who have received prior cisplatin chemotherapy.

Extended-field radiation therapy for carcinoma of the cervix.

The survival of cervical carcinoma patients with paraaortic/high common iliac nodal metastases was evaluated by retrospective chart review during a 13-year interval. Thirty-three patients with cervical carcinoma and surgically documented nodal metastases received primary, extended-field radiation therapy. Overall 2-year and 5-year actuarial survival rates after diagnosis were 37% and 31%, respectively. Survival was analyzed in terms of the variables patient age, clinical stage, tumor histologic type, the presence of enlarged paraaortic/high common iliac lymph nodes, the extent of nodal involvement (microscopic versus macroscopic), the presence of intraperitoneal disease, and whether intracavitary brachytherapy was administered. The use of intracavitary radiation therapy was associated with improved local control and survival (P = 0.017). None of the other variables were statistically related to patient survival. Twenty-two of the patients died of cervical cancer and five are surviving without evidence of cancer. Four patients died of intercurrent disease. Two patients developed bowel-related radiation complications; both patients received chemotherapy concurrent with the radiation therapy. One of the two patients died of radiation enteritis. The use of extended-field radiation therapy does benefit a small group of patients and may result in extended patient survival.

A patient with multiple, malignant melanomas of the lower genital tract.

Malignant melanomas of the female genital tract are uncommon lesions. A patient with multiple cutaneous, vulvar melanomas and a subsequent malignant melanoma of the cervix is described.

Rhabdomyosarcoma of the uterus in a postmenopausal patient.

Pure rhabdomyosarcomas of the female genital tract most commonly occur in infancy or childhood as sarcoma botryoides (embryonal rhabdomyosarcoma) and involve the vagina and cervix. Such tumors rarely occur in adults. A pure rhabdomyosarcoma of the uterus that arose in a postmenopausal patient is described. The pertinent literature is discussed.

Survival of patients with ovarian epithelial carcinomas after second-look laparotomy.

Survival of ovarian carcinoma patients undergoing second-look laparotomy after primary surgery and adjunctive chemotherapy was evaluated by retrospective chart review. From August 1976 to August 1987, 102 patients with stage I-IV disease underwent second-look laparotomy. Optimal tumor debulking and early (stage I or II) disease were positively correlated with a negative second-look laparotomy. Of the 49 patients with a "negative" second look, 15 demonstrated recurrent tumor from 12.5 to 52.5 months after laparotomy. Of the 15 recurrences, 6 were documented more than 3 years following second look. Half of the 28 patients with stage III disease and a "negative" second look have demonstrated recurrent tumor. Fifty-three patients (52%) were found to have residual disease at second-look laparotomy. Initial chemotherapy (melphalan or multiple agent) and the adequacy of primary debulking surgery (optimal vs suboptimal) were not significant factors contributing to patient survival after a positive second look. However, the size of residual disease at second-look laparotomy was a significant factor in subsequent patient survival (P less than or equal to 0.01). Fifteen patients were free of gross disease at laparotomy, but had residual tumor on microscopic examination of the specimens submitted. These patients had a 2-year actuarial survival of 78%. Forty-seven percent have survived 5 or more years after second look. Nineteen patients with tumor implants 2 cm or smaller had 2- and 5-year actuarial survivals of 61 and 31%, respectively. Nineteen patients with tumor nodules larger than 2 cm in diameter had a 2-year actuarial survival of 6%. Only 1 of 19 patients with nodules greater than 2 cm could be effectively redebulked.

Multimodality approach to a massive carcinoma of the vulva.

The presentation, combination therapy and clinical course of a patient with a massive vulvar carcinoma are described. Therapeutic aspects in the treatment of such advanced malignancies are considered. A multimodality approach to locally advanced, unresectable vulvar carcinomas may benefit this group of patients.

Stage II endometrial carcinoma treated with external-beam radiotherapy, intracavitary application of cesium, and surgery.

From September 1972 to September 1987, thirty-six patients with stage II carcinoma of the endometrium were treated with external-beam radiotherapy to the pelvis, a single intracavitary application of cesium-137, and extrafascial hysterectomy with adnexectomy. Patients were followed for a median of 54.4 months. Overall 2- and 5-year actuarial survival rates were 83 and 58%, respectively. Survival was analyzed in terms of the independent variables surgical stage, presence of a gross cervical lesion, and residual disease within the myometrium or cervix. Factors contributing to patients survival were analyzed by the log-rank method. The 12 patients with a gross cervical lesion had an adverse prognosis, as compared to those without such a lesion (P less than 0.05). Seven of the twelve patients (58%) with a cervical lesion at clinical staging demonstrated persistent or recurrent disease. The presence of extrauterine disease at surgery was a major prognostic factor in patient survival (P less than 0.01). All six patients with extrauterine disease expired 2.3 to 53.0 months after hysterectomy. Two patients with persistence of disease expired 2.3 and 7.5 months after hysterectomy. Eleven patients developed recurrent disease 2.1 to 56.5 months after hysterectomy. All presented with distant metastases. Four of the thirteen patients with persistent or recurrent disease had no residual tumor within the myometrium.

Assessment of pretreatment laparotomy in patients with cervical carcinoma prior to radiotherapy.

One hundred fifty-five patients with cervical cancer not amenable to radical surgery underwent selective, paraaortic lymphadenectomy and exploratory laparotomy prior to the initiation of radiotherapy. Fifty-one patients underwent transperitoneal lymphadenectomy; the remainder had the procedure performed using the extraperitoneal approach. Twenty-six patients (17%) were found to have metastatic disease to the paraaortic lymph nodes. The incidence of paraaortic metastases increased with advancing clinical stage. Twenty-four of the 26 patients were treated with extended-field radiotherapy which did not exceed 5100 cGy to the paraaortic region. Twenty-three percent of the patients with positive paraaortic nodes had documented intraperitoneal tumor. Two- and five-year actuarial survival rates for patients with paraaortic metastases were 35 and 27%, respectively. Approximately 4.6% of patients undergoing a selective paraaortic lymphadenectomy derived therapeutic benefit from the information supplied by the procedure. Using a Cox model, tumor histology, status of the paraaortic lymph nodes, tumor size, and presence of intraperitoneal disease were statistically significant prognostic factors in patient survival. Tumor size and presence of intraperitoneal disease were major predictors of patient survival.