David P. Warshal

Associations between ERBB2 amplification and progression-free survival and overall survival in advanced stage, suboptimally-resected epithelial ovarian cancers: A Gynecologic Oncology Group study

OBJECTIVE(S) The Gynecologic Oncology Group (GOG) examined the association between ERBB2 amplification and clinical covariates, tumor response, disease status post-chemotherapy, progression-free survival (PFS), and overall survival (OS) in epithelial ovarian cancer (EOC). METHODS Women with suboptimally-resected, advanced stage EOC who participated in GOG-111, a multi-center randomized phase III trial of cyclophosphamide+cisplatin versus paclitaxel+cisplatin, and provided a tumor block through the companion protocol GOG-9404 were eligible. ERBB2 amplification was examined using fluorescence in situ hybridization (FISH) with probes for ERBB2 and the centromere of chromosome 17 (CEP17). RESULTS ERBB2 amplification, defined as >2 copies of ERBB2/CEP17, was a rare event in EOC with 7% (9/133) of women exhibiting between 2.2 and 33.7 copies of ERBB2/CEP17, and was not associated with patient age, race, GOG performance status, stage, cell type, grade, measurable disease status, volume of ascites, tumor response or disease status post-chemotherapy. Women with >2 verses < or =2 copies of ERBB2/CEP17 did not have a reduced risk of disease progression (hazard ratio [HR]=0.56; 95% confidence interval [CI]=0.27-1.16; p=0.120) or death (HR=0.57; 95% CI=0.26-1.23; p=0.152), and ERBB2 amplification was not an independent prognostic factor for PFS or OS. ERBB2 amplification, defined as >4 copies of ERBB2/nuclei, was observed in 9% (12/133) of women with levels ranging from 4.2 to 49.2 copies of ERBB2/nuclei, and was associated with older age and volume of ascites, but not with the other clinical covariates or outcome. CONCLUSION(S) ERBB2 amplification is a rare event and has no predictive or prognostic value in suboptimally-resected, advanced stage EOC treated with platinum-based combination chemotherapy.

A phase II evaluation of weekly gemcitabine and docetaxel for second-line treatment of recurrent carcinosarcoma of the uterus: A gynecologic oncology group study

BACKGROUND The objective of this study was to estimate antitumor activity and toxicity of weekly docetaxel and gemcitabine as second-line chemotherapy for patients with recurrent uterine carcinosarcoma. METHODS Patients with recurrent carcinosarcoma of the uterus who had failed one regimen of chemotherapy, had a Gynecologic Oncology Group (GOG) performance status of 0-2 and had measurable disease were included. Treatment consisted of gemcitabine 600 mg/m(2) and docetaxel 35 mg/m(2) intravenously on days 1, 8 and 15 of a 28-day cycle until disease progression or intolerable adverse effects. This study employed an optimal but flexible two-stage design with an early stopping rule. If more than 3 out of 22-24 or more than 4 out of 25-29 patients responded, accrual to the second stage was to be initiated. RESULTS Twenty-eight patients were enlisted. Three patients were not eligible after pathology review. One patient was never treated. Twenty-four patients were evaluable. Nine patients had previous radiation therapy. There were no complete responses. Partial responses were seen in two patients (8.3%), stable disease in eight (33.3%) and progressive disease in 12 patients (50%). Two patients were not evaluable (8.3%). The median progression-free survival was 1.8 months. The median survival was 4.9 months. The treatment caused myelosuppression, mainly neutropenia, but also thrombocytopenia and anemia. Dose modifications became necessary in the majority of patients. In five patients, treatment was discontinued due to toxicity. CONCLUSIONS This regimen of docetaxel and gemcitabine is not active in patients with recurrent carcinosarcoma of the uterus as second-line chemotherapy.

Recurrent mild abruptio placentae occurring immediately after repeated electroconvulsive therapy in pregnancy

We present a case in which electroconvulsive therapy was performed repeatedly in pregnancy because of severe depression with psychotic features and failure of chemical treatment. Each electroconvulsive treatment was immediately followed by uterine contractions and active uterine bleeding, possibly representing recurrent abruptio placentae occurring in association with the treatment. Transient acute episodes of maternal hypertension between 180/90 and 190/100 mm Hg, documented within minutes after application of each electroconvulsive treatment, might explain the abruptio placentae manifested by active uterine bleeding and uterine hyperstimulation.

A Phase 2 Evaluation of Irofulven as Second-line Treatment of Recurrent or Persistent Intermediately Platinum-Sensitive Ovarian or Primary Peritoneal Cancer A Gynecologic Oncology Group Trial

This multicenter phase 2 trial was conducted by the Gynecologic Oncology Group to evaluate the activity and the safety of irofulven in patients with recurrent epithelial ovarian cancer. Eligible patients had documented recurrent ovarian cancer 6 to 12 months after receiving a front-line platinum-based regimen and no other chemotherapy. Patients were required to have measurable disease, performance status of 0 to 2, and adequate bone marrow, hepatic, and renal functions before study entry. The dose of irofulven was 0.45 mg/kg intravenously on days 1 and 8 every 21 days. Responses were defined by Response Evaluation Criteria in Solid Tumors. Fifty-five of 61 enrolled patients were evaluable for response and toxicity. There were 7 partial responses (12.7%), and 30 patients (54.6%) had stable disease. Median progression-free and overall survival were 6.4 months (1.3-37.5 months) and 22.1 months or more (2.8-57.8+ months), respectively. Patients received a median of 3 cycles (range, 1-21) of protocol therapy. Grade 4 hematologic toxicity was limited to reversible neutropenia and thrombocytopenia. Grade 4 nonhematologic toxicity was limited to one patient with anorexia and another with hypomagnesemia. Irofulven administered at this dose and schedule was well tolerated but had modest activity as a single agent.

A phase II evaluation of ixabepilone in the treatment of recurrent/persistent carcinosarcoma of the uterus, an NRG Oncology/Gynecologic Oncology Group study

BACKGROUND The primary objectives were to determine the objective response rate (ORR) and safety profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS. METHODS Patients had measurable disease; up to two prior chemotherapeutic regimens were allowed, but must have included a taxane. Women received ixabepilone 40mg/m2 as a 3hour IV infusion on day 1 of a 21daycycle. Treatment was continued until disease progression or unacceptable toxicity occurred. RESULTS Forty-two women were enrolled, with 34 eligible and evaluable. Median age was 68years. ECOG performance status was 0 in 56% of women, 38% had received radiation, and 15% had received 2 lines of chemotherapy. Overall ORR was 11.8% (4/34, 90% CI 4.2-25.1%); all were partial responses. Stable disease for at least 8weeks was achieved in 8 patients (23.5%). Median PFS and OS were 1.7mo and 7.7mo, respectively, with a median follow-up of 37mo. Six month PFS was 20.6%. Major grade≥3 toxicities were neutropenia (47%), fatigue (15%), dehydration (15%), hypertension (15%), and hyponatremia (15%); grade 2 peripheral neuropathy was reported in 18%. In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS. CONCLUSION In this cohort of women, single agent ixabepilone showed modest but insufficient clinical activity.

Interstitial pregnancy complicated by rectal bleeding

An interstitial pregnancy complicated by rectal bleeding is described. Despite modern imaging modalities, confounding features made preoperative diagnosis difficult. The pregnancy ruptured into the ileum. Ossified fetal skull bones and degenerated placental tissue were the only remains from the pregnancy.

Disease extent at secondary cytoreductive surgery is predictive of progression-free and overall survival in advanced stage ovarian cancer: An NRG Oncology/Gynecologic Oncology Group study

PURPOSE GOG 152 was a randomized trial of secondary cytoreductive surgery (SCS) in patients with suboptimal residual disease (residual tumor nodule >1cm in greatest diameter) following primary cytoreductive surgery for advanced stage ovarian cancer. The current analysis was undertaken to evaluate the impact of disease findings at SCS on progression-free survival (PFS) and overall survival (OS). METHODS Among the 550 patients enrolled on GOG-152, two-hundred-sixteen patients were randomly assigned following 3cycles of cisplatin and paclitaxel to receive SCS. In 15 patients (7%) surgery was declined or contraindicated. In the remaining 201 patients the operative and pathology reports were utilized to classify their disease status at the beginning of SCS as; no gross disease/microscopically negative N=40 (19.9%), no gross disease/microscopically positive N=8 (4.0%), and gross disease N=153 (76.1%). RESULTS The median PFS for patients with no gross disease/microscopically negative was 16.1months, no gross disease/microscopically positive was 13.5months and for gross disease was 11.7months, P=0.002. The median OS for patients with no gross disease/microscopically negative was 51.5months, no gross disease/microscopically positive was 42.6months and for gross disease was 34.9months, P=0.018. CONCLUSION Although as previously reported SCS did not change PFS or OS, for those who underwent the procedure, their operative and pathologic findings were predictive of PFS and OS. Surgical/pathological residual disease is a biomarker of response to chemotherapy and predictive of PFS and OS.

Cyclin D1 and p57 expression in advanced ovarian epithelial carcinoma: A GOG study.

5086 Background:The aim of this study was to investigate expression of cyclin D1 and p57 in advanced epithelial ovarian cancer and their association with progression free survival (PFS), overall survival (OS), clinical response and evidence of disease at second look laparotomy (SLL). METHODS Of 410 women in GOG-0111(a randomized study of cyclophosphamide/cisplatin vs. paclitaxel/cisplatin in stage III and IV ovarian cancer) 139 had available formalin-fixed and paraffin-embedded tumor blocks. Ninety-eight underwent immunocytochemical staining for cyclin D1 and 121 for p57. Cyclin D1 and p57 expression were dichotomized at their medians by percent of positive tumor cells. Fishers exact tests were used to compare patient characteristics. PFS and OS for each were compared using Cox proportional hazards models (unadjusted and adjusted for age and stratified by stage, grade, treatment, measurable disease, and histologic cell-type). Response to therapy and proportion with positive SLL were also compared. RESULTS Of 98 samples stained for cyclin D and 121 samples stained for p57, the median percent positive tumor cell expression was 4.47% for cyclin D (range 0.3-63.2%) and 72.6% for p57 (range 0.6-87.7%). Neither cyclin D1 nor p57 expression were significantly associated with patient characteristics including age, race, performance status, treatment arm, grade, histology, stage or amount of residual disease. In addition, neither was associated with other molecular markers including c-myc, p53, cyclin E, HER2, or p27. In unadjusted and adjusted models for PFS, there was no significant association with percentage of tumor cells positive for cyclin D1 (adjusted HR 1.21, 95% CI 0.73-2.00) or p57 (adjusted HR 0.85, 95% CI 0.54-1.34). OS was similarly not associated with cyclin D1 (adjusted HR 1.12, 95% CI 0.67-1.87) or p57 (adjusted HR 0.75, 95% CI 0.47-1.21) expression. There was also no association of either protein with clinical response (P=0.146 and P=0.433) or positive SLL (P=0.805 and P=0.476). CONCLUSIONS We found no significant association of cyclin D1 or p57 expression with PFS, OS, clinical response or positive SLL. This suggests that cyclin D1 and p57 are not useful prognostic markers in advanced epithelial ovarian cancer.

Endometrial carcinoma: The relevance of cervical cytology

In patients with endometrial carcinoma, preoperative identification of poor prognostic factors is helpful in planning therapy. Extended surgical staging, including pelvic and periaortic node dissection, is indicated in patients with deep myometrial invasion or high-grade tumor, or when other risk factors for extrauterine spread are present. In this study, cervical cytology was reviewed in 86 patients with endometrial carcinoma, all of whom underwent surgical staging, to correlate the cytologic results with surgical and pathologic findings. Cervical cytology was normal in 20 patients (23%), whereas suspicious or malignant endometrial cells were present in 23 and 43 cases (27 and 50%), respectively. Suspicious or malignant cervical cytology was associated with deeper myometrial invasion (P=.011), higher postoperative tumor grade (P=.006), positive peritoneal washings (P=.012), and more advanced stage by International Federation of Gynecology and Obstetrics criteria (P=.024). When compared with patients with normal cervical cytology, those who had malignant endometrial cells had over twice the risk of deep myometrial invasion (67 versus 30%), twice the risk of grade 2 or 3 tumor (60 versus 30%), and three times the risk of positive peritoneal washings (33 versus 10%). Seventy-four percent of patients with malignant cervical cytology were stage IC or more. In contrast, 70% of patients with normal cervical cytology were stage IA or IB. Patients with endometrial carcinoma who have malignant endometrial cells detected by cervical cytology are at increased risk of having a deeply invasive, high-grade, advanced-stage tumor, and therefore are more likely to require extended surgical staging