Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group.

PURPOSE: Progestins have definite activity against advanced or recurrent endometrial carcinoma. Both parenteral and oral progestins yield similar serum levels and response rates, which range from 18% to 34%. The one major study that used oral medroxyprogesterone acetate (MPA) noted a response rate at the lower end of the range (18%) and much poorer progression-free and overall survival times (4 and 10.5 months, respectively) than previously reported. The present study sought to confirm this earlier study of oral MPA, to assess the importance of prognostic factors such as histologic grade and receptor levels, and to determine whether a higher dose of MPA would yield a higher response rate. PATIENTS AND METHODS: Two hundred ninety-nine eligible women with advanced or recurrent endometrial carcinoma were randomized to receive oral MPA either 200 mg/d or 1, 000 mg/d until unacceptable toxicity intervened or their disease progressed. RESULTS: Among 145 patients receiving the low-dose regimen, there were 25 complete (17%) and 11 partial (8%) responses for an overall response rate of 25%. The 154 patients receiving the high-dose regimen experienced 14 (9%) complete and 10 (6%) partial responses for an overall response rate of 15%. Median durations of progression-free survival were 3.2 months and 2.5 months for the low-dose and high-dose regimens, respectively. Median survival durations were 11.1 months and 7.0 months, respectively. The adjusted relative odds of responding to the high-dose regimen compared with the low-dose regimen was 0.61 (90% confidence interval, 0.36 to 1.04). Prognostic factors having a significant impact on the probability of response included initial performance status, age, histologic grade, and progesterone receptor concentration. Compliance with oral therapy was documented with serum levels 1 month after starting therapy, when possible. MPA levels were commensurate with the assigned dose and schedule. CONCLUSION: Oral MPA is active against endometrial carcinoma. Response to progestin therapy is more frequent among patients with a well-differentiated histology and positive progesterone receptor status. This study provides no evidence to support the use of MPA 1,000 mg/d orally instead of MPA 200 mg/d orally. In fact, the trends suggest the opposite. The use of oral MPA 200 mg/d is a reasonable initial approach to the treatment of advanced or recurrent endometrial carcinoma, particularly those lesions that are well-differentiated and/or progesterone receptor-positive (> 50 fmol/mg cytosol protein). Patients with poorly differentiated and/or progesterone receptor levels less than 50 fmol/mg cytosol protein had only an 8% to 9% response rate.

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.

A phase II trial of merbarone (NSC 336628) in the treatment of recurrent epithelial ovarian carcinoma. A Gynecologic Oncology Group Study.

BACKGROUND: Patients with recurrent epithelial ovarian carcinoma who progress through a cisplatin-based regimen or recur less than 6 months after discontinuing cisplatin, have limited therapeutic options. The Gynecologic Oncology Group conducted a Phase II trial of merbarone in this patient population. METHODS: Twenty-seven patients with recurrent epithelial ovarian carcinoma who had previously received one prior cisplatin-based regimen were scheduled to receive 1000 mg/m2 of merbarone by continuous intravenous infusion through a central line each day for five days every four weeks. RESULTS: Of the 27 patients entered, one was ineligible because of wrong primary, and two never received the drug, leaving 24 patients evaluable for toxicity. Twenty of 24 were evaluable for response. The regimen was well tolerated with only one episode each of GOG grade 3 leukopenia (4%) or grade 4 granulocytopenia (4%). There was one episode (4%) of GOG grade 3 gastrointestinal toxicity. Prior to increasing the infusate concentration to 4 mg/ml, there was one episode (4%) of altered mental status which, in retrospect, may have been secondary to iatrogenic hyponatremia. There were two partial responses (10%) (95% confidence interval 1.2-31.7%). CONCLUSIONS: Merbarone exhibited minimal activity at this schedule in this pretreated group of patients with epithelial ovarian carcinoma.

Cytoreduction of small intestine metastases using the Cavitron Ultrasonic Surgical Aspirator.

The Cavitron Ultrasonic Surgical Aspirator was used to reduce the volume of the small intestine metastases in 37 patients. Thirty-four patients had epithelial carcinoma of the ovary, and one each had tubal adenocarcinoma, papillary peritoneal tumor, and mesothelioma. Thirty-one patients had stage IIIC disease, and six had stage IV. Initially, 18 patients had small bowel disease greater than 15 mm in diameter (of any single nodule), and 10 had disease 6-15 mm in diameter. After cytoreduction using standard means, 18 patients had disease greater than 15 mm in diameter, and 9 patients had disease 6-15 mm in greatest diameter. After using the Cavitron, 13 patients had no gross residual disease, and 24 patients had disease 1-5 mm in diameter. The Cavitron Ultrasonic Surgical Aspirator is invaluable to obtain minimal residual disease of small bowel metastases while avoiding intestinal resection.

Evaluation of the polymerase chain reaction for the detection of human papillomavirus from urine.

The ability to detect the presence of human papillomavirus (HPV)-DNA sequences in urine was evaluated using polymerase chain reaction (PCR). DNA was purified and extracted from urine samples, and subjected to 40 cycles of amplification using the consensus primer pair MY11 and MY09. Coamplification using the beta-globin primers, GH20 and PC04, was performed as an internal reaction control. Following assay optimization, urine samples from 22 women undergoing examination for cervical dysplasia were tested for the presence of HPV-DNA. PCR assay results were correlated with cytologic and histologic findings as well as ViraType assay results. Overall, HPV was detected by PCR in 16 (76%) of the interpretable samples. HPV sequences were detected in 13 (87%) of the 15 specimens from women showing evidence of condylomata, dysplasia, or invasive carcinoma. HPV was detected in 3 (50%) of the women whose cytologic or histologic results were either negative or showed benign atypia. Although the sample size in this study is small, our results show that HPV can be detected by PCR in a majority of individuals showing evidence of HPV infection. The method described provides a means for the clinical laboratory to detect a broad range of HPV types from using a sample obtained by noninvasive techniques. The ability to easily obtain urine would allow for increased numbers of individuals to be tested, and thus, aid in our understanding of HPV.

Randomized placebo-controlled multicenter evaluation of diethyldithiocarbamate for chemoprotection against cisplatin-induced toxicities.

PURPOSE: Diethyldithiocarbamate (DDTC) blocks cisplatin-induced toxicities in animal models without inhibiting antitumor effects. DDTC chemoprotection was tested in a randomized, multicenter, double-blind comparison versus placebo (PB) in patients with lung or ovarian cancer. Primary end points were nephrotoxicity, ototoxicity, neuropathy, and completion of therapy. PATIENTS AND METHODS: Between April 1990 and February 1992, 221 patients were registered with small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), or ovarian cancer. Cisplatin (100 mg/m2) and cyclophosphamide (in ovarian cancer) or etoposide (in lung cancer) were administered with either DDTC (1.6 g/m2 over 4 hours) or PB intravenously, every 4 weeks for a planned six cycles. RESULTS: At an interim safety analysis, data were available for 195 patients from the combined lung and ovarian cancer populations (PB, 99 patients; DDTC, 96 patients). Withdrawal for chemotherapy-induced toxicities occurred in 9% of PB-treated patients and 23% of DDTC-treated patients (P = .008). The mean cisplatin delivered dose-intensity (DDI) was 23 mg/m2/wk on both arms. However, the mean cisplatin cumulative dose delivered (CDD) was 379 mg/m2 on the PB arm, compared with 247 mg/m2 on the DDTC arm (P = .0001). At the time of interim analysis, 28% of PB-treated patients had completed all six cycles of therapy, compared with only 6% of DDTC-treated patients (P < .001). Although, clinical hearing loss, neuropathy, emesis, and myelosuppression were equivalent in the two treatment arms, DDTC-treated patients had more nephrotoxicity as determined by changes in serum creatinine concentration. Toxicities related to DDTC infusion included transient hypertension, flushing, and hyperglycemia. DDTC did not compromise response rates in either tumor type. CONCLUSION: This study did not demonstrate a significant chemoprotective effect against cisplatin-induced toxicities with the DDTC dose schedule tested. Patients who received DDTC received lower cumulative doses of cisplatin, but were more likely to be withdrawn from treatment early due to chemotherapy-related toxicities.

Laparoscopic silastic band sterilization failures.

Silastic band laparoscopic sterilization was introduced in the early 1970s as an alternative to unipolar cautery laparoscopy. Banding eliminates burn injury and reduces tubal destruction. However, in comparison with other methods, the success of Silastic banding may depend more on tubal morphology. This case-control study of 70 banding failures and 140 controls matched for age, gravidity, and date of procedure reveals that morphologic abnormalities of pelvic organs (adhesions or tubal thickening) or a history of a disease known to cause such abnormalities (pelvic inflammatory disease) increases the risk of sterilization failure. The risk of failure is further increased if the procedure is performed immediately postpartum or postabortion rather than as an interval procedure.

Brachial plexus neuropathies after advanced laparoscopic surgery.

A retrospective review of 3,200 advanced laparoscopic procedures demonstrated five brachial plexus injuries during a 5-month period in 1986 (0.16% incidence rate). Brachial plexus injury can occur during laparoscopic surgery using steep Trendelenburg's position with shoulder braces and the patient's arm extended at 90 degrees. Position modification can reduce the risk for upper extremity neuropathies.

Percutaneous endoscopic drainage gastrostomy in the treatment of gastrointestinal obstruction from intraperitoneal malignancy.

We evaluated the effectiveness of a percutaneous technique for placement of a drainage gastrostomy. Progressive dilatation of the abdominal and gastric walls was used to place a Malecot catheter (28 French). Endoscopic guidance assured proper placement and assisted in the dilatation. Fourteen drainage gastrostomy tubes were placed in 12 patients. The tube could not be placed in on additional patient with tumor infiltration into the anterior gastric wall. No surgical complications occurred, but there was one postoperative complication, peritonitis treated with antibiotics without catheter removal. All catheters provided unobstructed drainage and decompression of gastrointestinal obstruction. Percutaneous endoscopic drainage gastrostomy seems to be an effective means of palliating small-bowel obstruction and its complication rate appears low. This method may be suitable to replace open laparotomy techniques for gasrostomy placement.

A phase II trial of vincristine in advanced or recurrent endometrial carcinoma. A Gynecologic Oncology Group Study.

Thirty-three evaluable patients who had not received prior chemotherapy were entered on a study of vincristine therapy for advanced or recurrent endometrial carcinoma. Vincristine 1.4 mg/m2 was given weekly as an i.v. bolus for 4 weeks and then every other week. There was one complete response (CR) lasting 5 months. Five patients had partial responses (PR) lasting 3-18 months. The CR+PR rate was 18% (95% confidence interval for CR+PR was 7-36%). Thirteen patients (38%) had stable disease from 2-28 months, and 14 had progressive disease. The major toxicity was neurological, with 11 patients having grade 2 or 3 peripheral neuropathy. Vincristine at this dose and schedule has modest activity, but troublesome toxicity in advanced or recurrent endometrial carcinoma.

Aging and development of ovarian epithelial carcinoma: the relevance of changes in ovarian stromal androgen production.

There are three types of ovarian neoplasms: (1) Those which arise from the surface epithelium covering the ovary. (2) Those which are derived from the cortical mesenchymal stroma. (3) Those which develop from germ cells. Our laboratory has concentrated its effort on solid tumors in women of the first type, epithelial, which has the highest incidence and is the most lethal. Development of these tumors is correlated with aging in the ovary. They form primarily during the perimenopause. Among women, 64% of the total ovarian cancer cases are diagnosed between ages 41 and 60 years. Our approach has been to establish stable tumor cell lines from patient specimens for use as in vitro models. We have investigated the response of these cells to steroid hormones because we hypothesized that these tumors retain some metabolic characteristics which are specific to the ovary. Our data demonstrate that testosterone and androstenedione, but not cortisol, inhibited proliferation of ovarian tumor cells in vitro by a mechanism which was independent of steroid receptors. These androgens are routinely synthesized and secreted by human ovary, and in the menopausal ovary the primary source of androgen is the stromal cell compartment. Because a relatively high local concentration of ovarian androgen exists in vivo, it is possible that androgen may suppress ovarian epithelial carcinoma in women as well. If it does, then development of this carcinoma may be facilitated when the postmenopausal ovary fails to produce adequate androgen during postreproductive years.

Ultrasonic surgical aspirator in cytoreduction of splenic metastases to avoid splenectomy.

The Cavitron Ultrasonic Surgical Aspirator (Cavitron) was used to reduce the volume of splenic metastases in seven patients. Six patients had epithelial carcinoma of the ovary, and one had peritoneal mesothelioma. All patients had stage IIIC disease. Initially, six patients had malignant disease > 15 mm in diameter (of any single nodule), and one had disease 6-15 mm in diameter. In order to avoid resection of the spleen, cytoreduction could not be performed by standard means. After using the Cavitron, three patients had no gross residual disease, and four patients had disease 1-5 mm in diameter. No complication resulted from cytoreduction of splenic disease using the Cavitron, and splenectomy was not performed in any case. The Cavitron is invaluable in obtaining minimal residual disease of splenic metastases without performing splenectomy.

Granulocytic sarcoma of the uterine cervix--literature review of granulocytic sarcoma of the female genital tract.

Granulocytic sarcoma is an extramedullary tumor of malignant granulocytic progenitor cells that accompanies, heralds, or signals relapse of acute myelogenous leukemia (AML), or indicates blastic transformation of a chronic myeloproliferative disorder. We describe a case involving the uterine cervix of a 51-year-old woman that led to the diagnosis of AML. Granulocytic sarcoma can occur in the female genital tract and may be the first clinically significant manifestation of a hematologic malignancy. The salient findings in 28 reported cases from 12 different countries are reviewed. Awareness of this lesion is important for all medical personnel involved in the health care of women.

Endometrial adenocarcinoma without prior hormone replacement in a diabetic patient with gonadal dysgenesis.

Patients with dysgenetic gonads and Turner syndrome are unlikely to develop endometrial carcinoma unless they have received unopposed estrogen replacement therapy. This case describes a 54-year-old woman with Turner syndrome and primary amenorrhea who developed adenocarcinoma of the endometrium without having received hormone replacement. Vaginal bleeding, a pelvic mass, and sepsis were the presenting symptoms. The patient also had diabetes mellitus and hypothyroidism. Polyglandular endocrine patterns are known to occur with a high frequency in these patients. The woman's chromosome studies revealed a modified 46,X,i(Xq) (isochromosome X). This is the first report of an isochromosome X patient to develop endometrial cancer without receiving estrogen replacement. The etiology of this rare case may be an increased propensity for patients with X-chromosome deletions to develop neoplasms in general, or extragonadal estrogen production.

Erythrocytosis associated with a placental-site trophoblastic tumor.

We present a case of placental-site trophoblastic tumor associated with erythrocytosis. This 42-year-old woman had persistent amenorrhea and low elevations of her hCG titer after term delivery of a healthy female infant. The woman was noted to have polycythemia of uncertain etiology and was treated with serial phlebotomy. Placental-site trophoblastic tumor was diagnosed and hysterectomy was performed, with subsequent resolution of the polycythemia. Although erythrocytosis has been reported with other gynecologic tumors, this is the first reported association with a placental-site trophoblastic tumor. A role has been suggested for placental lactogen in erythropoiesis during pregnancy based on previous animal studies. Diffuse positive staining for hPL is characteristic of placental-site trophoblastic tumors. We postulate that hPL may have played an ancillary role to erythropoietin in the erythrocytosis demonstrated in this case. Spider angiomata and splenomegaly are interesting clinical features previously described in association with placental-site trophoblastic tumors, and were demonstrated in this patient.

Squamous cell carcinoma of the endometrium presenting as peritonitis with small bowel obstruction.

Squamous carcinoma primary in the endometrium has been rarely reported. Diagnosis of this condition requires adherence to strict histologic criteria. Most patients are postmenopausal at presentation, and long-term survival is poor. We present a patient with peritonitis and small bowel obstruction. Chemotherapy was given after disease recurrence and was ineffective. Receptor data and serum markers were obtained.

Treatment of urinary infections in pregnancy using single versus 10-day dosing.

Pregnant patients with symptomatic and asymptomatic urinary tract infections were treated with a long and a short antibiotic regimen. Two hundred two patients were randomized prospectively to a single oral dose of 3.5 g ampicillin plus 1 g probenecid (98 patients) versus 500 mg ampicillin orally four times a day for 10 days (104 patients). The multiple-dose cure rate was statistically significantly better than that of the single-dose regimen (67.3% versus 57.1%, respectively). Interestingly, for resistant organisms, the cure rate for the long and short regimens was similar (48% versus 43%, respectively). In vitro susceptibility testing does not appear to be a good predictor of cure, at least for the single-dose group. Single-dose therapy with ampicillin and probenecid does not provide an optimal cure rate or prevent reinfection during pregnancy. Possible reasons for these findings are discussed.

Recurrent necrotizing fasciitis of the vulva. A case report.

Necrotizing fasciitis most often occurs in the context of prior trauma or surgery. Predisposing medical conditions include diabetes mellitus, arteriosclerosis, obesity, hypertension and prior irradiation. De novo occurrence in the vulva, in the absence of prior injury, surgery or irradiation, has been reported rarely. Necrotizing fasciitis of the vulva in the diabetic patient may have an insidious onset but requires an early diagnosis and aggressive surgical episode of fasciitis occurred in an obese, diabetic woman. Aggressive, wide excision of all infected vulvar, mons and thigh tissue, followed by aggressive medical and surgical postoperative care, resulted in minimal morbidity. Prompt recognition and aggressive care are required to treat this condition.

Use of the intestinal isolation bag in gynecologic surgery.

Exposure of the operative site during laparotomy is, at times, suboptimal. The major viscera requiring retraction out of the operative field are the small intestines. Usually, multiple cloth laparotomy packs are used to compress and displace the intestines. We describe the use of an intestinal isolation bag to house the small intestines and keep them out of the operative field. Using this technique, laparotomy packs are not required. Because the bag itself takes up very little space, the size of the operating field is not compromised. In addition, the bag does not abrade or desiccate the bowel, potentially reducing serosal injury and adhesion formation.