Low-grade endometrial stromal sarcoma of the ectocervix after therapy for breast cancer.

OBJECTIVE: Low-grade endometrial stromal sarcoma is an uncommon, indolent uterine sarcoma that can arise in extrauterine locations. The objective of this study was to report on a previously unpublished site of origin for a low-grade endometrial stromal sarcoma. METHODS: A case of a low-grade endometrial stromal sarcoma arising in the ectocervix after goserelin hormonal therapy for breast cancer was studied. RESULTS: Low-grade endometrial stromal sarcoma can arise in the ectocervix even in the absence of endometriosis. CONCLUSION: Low-grade endometrial stromal sarcoma should be included in the differential diagnosis of sarcomas of the ectocervix.

Granulocyte-macrophage colony-stimulating factor. Preliminary observations on the influences of dose, schedule, and route of administration in patients receiving cyclophosphamide and carboplatin.

BACKGROUND: In an attempt to learn how best to administer granulocyte-macrophage colony-stimulating factor (GMCSF), the authors performed a Phase I study of this agent. They were interested in the influences of dose, schedule, and route of administration on the effects of GMCSF in patients receiving standardized 1-day regimens of cyclophosphamide (CYCLO) and carboplatin (CBDCA). METHODS: Between June 1988 and March 1991, 57 patients with advanced cancer received GMCSF in association with CYCLO 1 g/m2 plus CBDCA 225-700 mg/m2. After the first dose escalation to 300 mg/m2 of CBDCA, patients who had previously received chemotherapy or radiation therapy were excluded. GMCSF was administered in three different doses, five different schedules, and by two different routes. Altogether, 17 different treatment groups were observed. In addition, 24-hour GMCSF serum concentration curves were charted in four patients. RESULTS: Using four sequential groups of three patients each who had received myelosuppressive treatment, treatment with CYCLO 1 g/m2 and CBDCA 225 mg/m2, the apparent superiority of daily subcutaneous injection over 30-minute daily IV infusion of GMCSF was demonstrated graphically. Subsequently, the authors observed apparent enhancement of GMCSF effects beyond those produced by the initially selected 20-day basic 10 micrograms/kg daily SC regimen beginning 2 days after chemotherapy. When administered SC every 12 hours for 14 days beginning the day after chemotherapy, GMCSF appeared to ameliorate the severity of both leukopenia and thrombocytopenia. These effects permitted escalation of the CBDCA dose to 700 mg/m2 (with 1 g/m2 of CYCLO) before cytotoxic tolerance limits were reached. Graphic small group comparisons suggest that GMCSF given SC in doses of 5 micrograms/kg twice daily may produce comparable leukocyte and platelet support after chemotherapy with lower toxicity than occurs from higher doses. Prechemotherapy priming with GMCSF twice daily for an additional 4 days (days -6 to -3) seems to ameliorate postchemotherapy cytopenias further but at the cose of some increased risk of GMCSF toxicity. Although most of the toxic effects of moderate-dose GMCSF are controlled by antihistamines and ibuprofen, oral glucocorticoids (e.g., prednisone, 10 mg twice daily during the second week of GMCSF administration) may be required in patients with serositis, pulmonary infiltrates, or severe skin eruptions. CONCLUSIONS: Our observations suggest that GMCSF should be administered SC in doses of approximately 5 micrograms/kg every 12 hours for 10-14 days beginning the day after chemotherapy. Prechemotherapy priming with these same doses for four additional days (days -6 to -3) may additionally ameliorate postchemotherapy leukopenia and thrombocytopenia, but with increased risk of toxicity.

Evaluation of treatment and survival after positive second-look laparotomy.

During the 9-year interval 1977 through 1985, of 250 patients undergoing second-look laparotomy, 116 (46%) were found to have clinically occult ovarian carcinoma. Salvage therapy consisted of external irradiation in 37, intraperitoneal 32P in 12, chemotherapy in 63, and no therapy in 3 or other therapy in 1. Eligible follow-up time ranged from 1 to 9 years. The Kaplan-Meier projected median time-to-progression and survival were 15 and 22.5 months, respectively, with 4-year progression-free and overall survival rates being 21 and 27%, respectively. Survival was independent of the original stage of disease but was significantly influenced by histologic grade and microscopic (55%) versus macroscopic (19%) residual tumor after the laparotomy. Projected 4-year salvage rates in patients with microscopic or residual disease less than or equal to 5 mm was 72, 39, and 19% for intraperitoneal 32P, external irradiation (33/37, whole abdominopelvic), and chemotherapy, respectively. However, multivariable analysis demonstrated that histologic grade and isotope therapy retained independent influence on survival, but no therapeutic advantage for external irradiation over chemotherapy was demonstrable. Furthermore, use of regimens that were identical to, partially altered from, or different from the first-trial agents did not affect chemotherapy salvage rates.

Phase II studies of bleomycin, cyclophosphamide, doxorubicin and cisplatin, and bleomycin and cisplatin in advanced cervical carcinoma.

In a randomized phase II trial of two cisplatin-based chemotherapy regimens, 45 patients with advanced cervical carcinoma received a combination of bleomycin, cyclophosphamide, doxorubicin, and cisplatin (BCAP), and 45 others received bleomycin plus cisplatin (BP). BCAP was repeated every 4 weeks, and BP was given at 3-week intervals. Although 19 of 43 (44%) evaluable patients receiving BCAP and 16 of 42 (38%) evaluable patients receiving BP experienced tumor regression, only 22% of those receiving BCAP and 21% of those on BP survived 1 year after beginning treatment. Among bidimensionally measurable patients, 15 of 27 (56%) and 8 of 25 (32%) receiving BCAP and BP, respectively, achieved tumor regression. One patient died of bleeding resulting from severe myelosuppression on BCAP, and two others succumbed to pulmonary toxicity of bleomycin on the BP regimen. Although active against cervical carcinoma, these regimens have limited therapeutic value at this advanced stage of the disease.

Randomized phase II studies of cisplatin and a combination of cyclophosphamide-doxorubicin-cisplatin (CAP) in patients with progestin-refractory advanced endometrial carcinoma.

Between May 1980 and September 1983, 30 progestin-refractory patients with metastatic endometrial carcinoma were assigned at random to treatment groups receiving either cisplatin (CDDP) 60 mg/m2 every 3 weeks or a combination of cyclophosphamide, doxorubicin, and cisplatin every 4 weeks in doses of 400, 40, and 40 mg/m2, respectively. Those who failed cisplatin were then offered cyclophosphamide 500 mg/m2 plus doxorubicin 40 mg/m2 every 3 weeks. Reduced doses were utilized in both of the combination regimens for patients who had received extensive pelvic radiation. Of the 14 patients initially receiving cisplatin alone, 3 experienced objective tumor regression. One of these three and one other who failed primary cisplatin therapy later responded favorably to cyclophosphamide plus doxorubicin as secondary treatment. Among the 16 patients who took all three drugs simultaneously (CAP) 5 experienced objective partial tumor regression. Survival experience for these relatively late-stage patients has been uniformly poor, with only 7 and 12% surviving at 2 years after beginning CDDP and CAP, respectively. Thus, while cisplatin is clearly an active agent against endometrial carcinoma, its therapeutic index as a single drug or in combination (CAP) is not adequate to preclude new-agent Phase II studies early in patients with advanced disease.

Pilot study of cyclophosphamide plus carboplatin in advanced ovarian carcinoma.

Six patients with histologically proven stage III-IV ovarian carcinoma received carboplatin (CBDCA) (150 mg/m2) plus cyclophosphamide (1000 mg/m2) monthly for 1 year unless disease progressed earlier. Six other patients received CBDCA (225 mg/m2) with the same cyclophosphamide dose monthly. Continued treatment with the higher CBDCA dose was not tolerable because of myelosuppression, but no other dose-limiting toxic effect was observed. Complete tumor regression was proven at secondary laparotomy in six of the 12 patients, and five of these remain disease-free from 26+ to 28+ months after beginning chemotherapy.

Comparison of cyclophosphamide plus cisplatin versus hexamethylmelamine, cyclophosphamide, doxorubicin, and cisplatin in combination as initial chemotherapy for stage III and IV ovarian carcinomas.

Among 187 women with stage III and IV ovarian carcinoma who participated in this comparative clinical trial, 181 were eligible for analysis. Of these patients, 89 received monthly treatment with CP [cyclophosphamide (1 g/m2) plus cisplatin (60 mg/m2)] and 92 received monthly treatment with HCAP [hexamethylmelamine (150 mg/m2/day X 7), cyclophosphamide (400 mg/m2), doxorubicin (30 mg/m2), and cisplatin (60 mg/m2)]. All treatments were administered iv on Day 1 of each monthly treatment cycle, except for hexamethylmelamine, which was administered orally on Days 2-8. With a median follow-up time of 30 months, survival curves for the two treatment groups were almost identical, as were their times to progression [estimated median survival, 24.6 months (Kaplan-Meier)]. Patient characteristics which significantly influenced survival were age, degree of histologic differentiation, extent of residual disease, stage of disease, and histologic type. Results of posttreatment laparotomies have been equal for the two treatment groups. Toxic effects of the two regimens have been similar, except for more frequent, more severe, and earlier neurotoxicity among patients treated with HCAP. Of the two regimens, CP has the better therapeutic index.

Effects of progestational agents in treatment of endometrial carcinoma.

Progestational agents induced an objective response in 11.2% of 155 patients with advanced primary or recurrent endometrial carcinoma. Response rates decreased with decreasing tumor differentiation from 40% with Broders grade 1 lesions to 17.5, 2.4, and 0%, respectively, with grades 2, 3, and 4. 17 alpha-Hydroxyprogesterone caproate (Delalutin), 6,17 alpha-dimethyl-6-dehydroprogesterone (Colprone), and 6-methyl-6-dehydroprogesterone acetate (Megace) were the progestogens used; there was no significant advantage for any one agent. Overall, survival after initiation of hormone therapy was 40% at one year, 19% at two years, and 8% at five years. Survival was highly dependent on the degree of tissue differentiation (P less than .001) and was influenced significantly by the estimated tumor volume at the start of therapy (P less than .01) and by the time interval from primary treatment to the beginning of hormone therapy (P less than .01).

Upper genital tract abnormalities and pregnancy outcome in diethylstilbestrol-exposed progeny.

Previous studies have suggested that there is an association between genital tract abnormalities and pregnancy outcome in women exposed to diethylstilbestrol (DES) in utero. In a collaborative study, 676 DES-exposed women had hysterosalpingographic examinations, and the findings were related to the outcome of pregnancy in 327 of these women. The findings revealed that (1) there is a considerable variation of frequency of different types of upper genital tract anomalies in women from different sources and with different motivations for enrollment in the study, (2) the presence of structural cervical changes and vaginal epithelial changes are markers for the likelihood of abnormalities in the uterine fundus, (3) women with upper genital tract abnormalities have increased odds for poor pregnancy outcome as compared to women with normal hysterosalpingographic findings, and (4) although some abnormalities were most often or consistently associated with poor pregnancy outcome, no specific changes could be related to specific types of pregnancy outcomes.

Structural anomalies of the cervix and vagina in women enrolled in the Diethylstilbestrol Adenosis (DESAD) Project.

Among women exposed in utero to diethylstilbestrol (DES) and enrolled in the Diethylstilbestrol Adenosis (DESAD) Project, structural anomalies of the cervix or vagina were found in 25% of the 1,655 subjects identified by review of prenatal records, 43% of the 800 who themselves requested entry into the project, and 49% of the 1,089 referred by physicians but in only 2% of the 963 control subjects. Among the 367 cases found by record review to have complete information on the DES exposure, multivariate analysis indicated close association of the anomalies with the gestational week of first exposure and the total dose. Also, the prevalence rate of the anomalies was lower among subjects who had been pregnant and higher among those with later age at menarche.

Maturation of vaginal and cervical epithelium in women exposed in utero to diethylstilbestrol (DESAD Project).

A total of 452 women with documented exposure in utero to diethylstilbestrol (DES) with epithelial findings present at the time of their initial examination have been evaluated prospectively to determine whether these findings changed over a period of 3 years. The examinations were all performed according to a strict protocol. Findings present at the time of the third annual examination were verified at a fourth examination. A verified decrease in the extent of epithelial findings occurred in 29.2% of these women and a verified increase in 6.6%; 53.1% had no change in the extent of epithelial findings, and 11.1% had a change that could not be verified at the time of the fourth visit. Analysis of many variables failed to identify a strong association between any variable and a decrease in the extent of the findings. It appears that the most important factor in the occurrence of changes in DES-associated findings is the passage of time.

Different chemotherapeutic sensitivities and host factors affecting prognosis in advanced ovarian carcinoma versus minimal residual disease.

Treatment of patients with advanced ovarian carcinoma (stages IIIB and IV) using either cyclophosphamide alone (1 g/m2) or cyclophosphamide (500 mg/m2) plus adriamycin (40 mg/m2) by iv injection every 3 weeks each produced partial regression in approximately one third of the patients. Survival curves and time-to-progression curves for the two regimens were nearly identical in these patients with advanced disease. These same regimens produced different results when used monthly in patients who had minimal residual disease (stages II and IIIA). In patients with minimal residual disease the therapeutic index of the combination regimen was superior to that of cyclophosphamide alone. Prognosis was better overall among patients with minimal residual disease than among patients with advanced disease. Within the minimal-disease group grossly complete excision of tumor prior to chemotherapy was associated with still better prognosis. Among patients with advanced disease, prognosis was significantly better for older patients despite their generally less favorable performance scores. Much of this prognostic superiority appeared to be related to menopausal status and presumably to the depletion of endogenous estrogens in the older patients.

The retained cervical stump. A 25-year experience.

During a 25-year period on one service at the Mayo Clinic, 262 cervical stumps were removed surgically: 208 vaginally and 54 abdominally. In this series, 46 patients had malignancy of the cervical stump. When a cervical stump is present, it most often can be expeditiously removed during the course of additional vaginal repairs with extremely few risks and complications, and low morbidity.