John T. Soper

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.

Retrospective Analysis of Selective Lymphadenectomy in Apparent Early-Stage Endometrial Cancer

PURPOSE Selective lymphadenectomy is widely accepted in the management of endometrial cancer. Purported benefits are individualization of adjuvant therapy based on extent of disease and resection of occult metastases. Our goal was to assess effects of the extent of selective lymphadenectomy on outcomes in women with apparent stage I endometrial cancer at laparotomy. PATIENTS AND METHODS Patients with endometrial cancer who received primary surgical treatment between 1973 and 2002 were identified through an institutional tumor registry. Inclusion criteria were clinical stage I/IIA disease and procedure including hysterectomy and selective lymphadenectomy (pelvic or pelvic + aortic). Exclusion criteria included presurgical radiation, grossly positive lymph nodes, or extrauterine metastases at laparotomy. Recurrence and survival were analyzed using Kaplan-Meier analysis and Cox proportional hazards model. RESULTS Among 509 patients, the median number of lymph nodes removed was 15 (median pelvic, 11; median aortic, three). Pelvic and aortic node metastases were found in 24 (5%) of 509 patients and 11 (3%) of 373 patients, respectively. Patients with poorly differentiated cancers having more than 11 pelvic nodes removed had improved overall survival (hazard ratio [HR], 0.25; P < .0001) and progression-free survival (HR, 0.26; P < .0001) compared with patients having poorly differentiated cancers with 11 or fewer nodes removed. Number of nodes removed was not predictive of survival among patients with cancers of grade 1 to 2. Performance of aortic selective lymphadenectomy was not associated with survival. Three (27%) of 11 patients with microscopic aortic nodal metastasis are alive without recurrence. CONCLUSION These data add to the literature documenting the possible therapeutic benefit of selective lymphadenectomy in management of patients with apparent early-stage endometrial cancer.

Overexpression of HER-2/neu in endometrial cancer is associated with advanced stage disease.

Prior studies have shown that overexpression of HER-2/ neu occurs in one third of breast and ovarian cancers and that overexpression is associated with poor prognosis. We used a monoclonal antibody to assess immunohistochemically the level of HER-2/ neu expression in normal and malignant endometrium. In 24 normal endometrial samples light to moderate (1+ to 2+) staining for HER-2/ neu was seen in the glands, and there was no variation in intensity of staining during the menstrual cycle. Among 95 endometrial adenocarcinomas, nine (9%) were found to have heavier staining for HER-2/ neu than was seen in normal endometrium (3+). High expression of HER-2/ neu was found in 27% of patients with metastatic disease compared with 4% of patients with disease confined to the uterus (p neu expression also was associated with absence of estrogen receptor (p neu overexpression in endometrial cancer.

Phase III trial of intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody in patients with epithelial ovarian cancer after a surgically defined complete remission.

PURPOSE This was a multinational, open-label, randomized phase III trial comparing yttrium-90-labeled murine HMFG1 (90Y-muHMFG1) plus standard treatment versus standard treatment alone in patients with epithelial ovarian cancer (EOC) who had attained a complete clinical remission after cytoreductive surgery and platinum-based chemotherapy. PATIENTS AND METHODS In total, 844 International Federation of Gynecology and Obstetrics stage Ic to IV patients were initially screened, of whom 447 patients with a negative second-look laparoscopy (SLL) were randomly assigned to receive either a single dose of 90Y-muHMFG1 plus standard treatment (224 patients) or standard treatment alone (223 patients). Patients in the active treatment arm received a single intraperitoneal dose of 25 mg of 90Y-muHMFG1 (target dose 666 MBq/m2). The primary end point was length of survival; secondary end points included time to relapse and safety. The study had an 80% power to detect a 15% change in survival. RESULTS After a median follow-up of 3.5 years (range, 1 to 6 years), 70 patients had died in the active treatment arm compared with 61 patients in the control arm. Cox proportional hazards analysis of survival demonstrated no difference between treatment arms. In the study drug arm, 104 patients experienced relapse compared with 98 patients in the standard treatment arm. No difference in time to relapse was observed between the two study arms. Active therapy was associated with occasional grade 3 or 4 thrombocytopenia and neutropenia and grade 1 or 2 GI symptoms, abdominal discomfort, arthralgia, and myalgia. CONCLUSION A single IP administration of 90Y-muHMFG1 to patients with EOC who had a negative SLL after primary therapy did not extend survival or time to relapse.

Influence of cytoplasmic steroid receptor content on prognosis of early stage endometrial carcinoma

The clinicopathologic associations and effect on prognosis of cytoplasmic steroid receptor content were studied in 168 patients with clinical Stage I and II endometrial carcinoma. Cytoplasmic estrogen receptor status was associated (p less than 0.01) with histologic differentiation, nuclear differentiation, and histologic documentation of extrauterine metastases. Progesterone receptor status was related (p less than 0.05) to histologic differentiation and histologic cell type, and combined estrogen receptor/progesterone receptor status was associated (p less than 0.05) with histologic differentiation, peritoneal cytology, extrauterine metastases, and histologic cell type among the 105 patients who had determination of both estrogen and progesterone receptors. Single-factor analysis revealed significant (p less than 0.05) effects of estrogen receptor status, progesterone receptor status, and estrogen receptor/progesterone receptor status on disease-free survival. All other clinicopathologic features significantly (p less than 0.05) affected prognosis, except for peritoneal cytology. With use of stepwise regression analysis of proportional hazards, estrogen receptor, progesterone receptor, and combined estrogen receptor/progesterone receptor status were significant independent prognostic factors, replacing histologic assessment of glandular or nuclear differentiation in the models. These data suggest that receptor status of primary endometrial carcinomas provides important information relevant to tumor behavior which complements the information provided by conventional clinicopathologic analysis.

Multivariable analysis of DNA ploidy, p53, and HER-2/neu as prognostic factors in endometrial cancer

Background. Several molecular‐genetic alterations in endometrial cancers, including aneuploidy and aberrant expression of p53 and HER‐2/neu, have been associated with poor prognosis. To determine the importance of molecular‐genetic factors relative to more traditional surgical‐pathologic prognostic factors, a multivariable analysis was performed.

Tamoxifen in the Treatment of Advanced or Recurrent Endometrial Carcinoma: A Gynecologic Oncology Group Study

PURPOSE In two large Gynecologic Oncology Group studies of patients with advanced or recurrent endometrial carcinoma and no previous systemic therapy, progestins have demonstrated activity against advanced or recurrent endometrial carcinoma with response rates between 15% and 25%. Tamoxifen has been reported as variously active or inactive with or without previous systemic therapy. The purpose of this study was to determine whether tamoxifen exhibits enough activity in patients with advanced or recurrent endometrial carcinoma, who have not received systemic therapy, to warrant a phase III trial. PATIENTS AND METHODS Sixty-eight eligible patients with advanced or recurrent endometrial carcinoma received oral tamoxifen 20 mg bid until toxicity was unacceptable or disease progressed. RESULTS Three complete (4%) and four partial (6%) responses were observed for an overall response rate of 10% (90% confidence interval [CI], 5.7% to 17.9%). Patients with tumors that were more anaplastic tended to respond less frequently. The median progression-free survival for all 68 eligible patients was 1.9 months (90% CI, 1.7 to 3.2 months). The median survival was 8.8 months (90% CI, 7.0 to 10.1 months). CONCLUSION Tamoxifen demonstrated modest activity at best against endometrial carcinoma and does not warrant further investigation as a single agent for this disease. Ongoing trials will assess the sequential use of tamoxifen and progestational agents.

Adjuvant radiotherapy following radical hysterectomy for patients with stage IB and IIA cervical cancer

Abstract From 1971 through 1984, 320 women underwent radical hysterectomy as primary therapy of stage IB and IIA cervical cancer. Two hundred forty-eight patients (78%) were treated with surgery alone and 72 patients (22%) received adjuvant postoperative external-beam ratiotherapy. Presence of lymph node metastasis, large lesion (>4 cm in diameter), histologic grade, race (non-caucasian), and age (>40 years) were significant poor prognostic factors for the entire group of patients. Patients treated with surgery alone had a better disease-free survival than those who received combination therapy ( P

A randomized trial of low-dose heparin and intermittent pneumatic calf compression for the prevention of deep venous thrombosis after gynecologic oncology surgery.

OBJECTIVE Our aim was to determine the relative efficacy and complications of low-dose heparin and intermittent pneumatic calf compression for the prevention of postoperative venous thrombosis in patients undergoing surgery for gynecologic malignancy. STUDY DESIGN Randomized trial comparing 107 patients treated with low-dose heparin to 101 patients treated with intermittent pneumatic calf compression was performed. All patients were evaluated with iodine-125 fibrinogen scanning of the legs. Clinical and laboratory variables associated with bleeding complications were recorded prospectively. RESULTS Venous thrombosis was diagnosed in seven patients receiving low-dose heparin and in four receiving intermittent pneumatic calf compression (p = 0.54). Low-dose heparin patients received more blood transfusions postoperatively (p = 0.02), had increased volume of retroperitoneal drainage (p = 0.02), and the activated partial thromboplastin time was more frequently prolonged (p = 0.001). CONCLUSIONS Low-dose heparin and intermittent pneumatic calf compression provide similar reduction in reducing the incidence of postoperative venous thrombosis. However, low-dose heparin is more frequently associated with postoperative bleeding complications.

Pelvic exenteration: Factors associated with major surgical morbidity

Sixty-nine women underwent pelvic exenteration at Duke University Medical Center from 1970 through 1987. The operative mortality rate was 7.2% with a trend toward a reduction during the course of the study. One or more serious gastrointestinal or genitourinary surgical complication occurred in 26 (38%) patients and 20 (29%) required reoperation for these complications. There was a trend (P less than 0.1) toward an increase in surgical complications among patients who received prior radiation therapy and those requiring urinary diversion, with a decrease among those who underwent gracilis flap pelvic reconstruction. Patients with sigmoid or ileal conduits had a significantly higher incidence of severe surgical complications than those with transverse colon conduits or posterior exenteration alone (P less than 0.05). Those in whom an ileal conduit was constructed without gracilis flap pelvic reconstruction had significantly more surgical morbidity compared to those who underwent pelvic reconstruction or received a transverse colon conduit (P less than 0.05). Multiple changes in technique since 1978 including (1) the routine use of surgical staplers for bowel resection and anastomosis, (2) the introduction of the transverse colon conduit, and (3) the use of gracilis flap for pelvic reconstruction have combined to produce a significant (P less than 0.05) decrease in life-threatening surgical complications.