Ellen M. Hartenbach

Phase III Trial of Carboplatin and Paclitaxel Compared With Cisplatin and Paclitaxel in Patients With Optimally Resected Stage III Ovarian Cancer: A Gynecologic Oncology Group Study

PURPOSE In randomized trials the combination of cisplatin and paclitaxel was superior to cisplatin and cyclophosphamide in advanced-stage epithelial ovarian cancer. Although in nonrandomized trials, carboplatin and paclitaxel was a less toxic and highly active combination regimen, there remained concern regarding its efficacy in patients with small-volume, resected, stage III disease. Thus, we conducted a noninferiority trial of cisplatin and paclitaxel versus carboplatin and paclitaxel in this population. PATIENTS AND METHODS Patients with advanced ovarian cancer and no residual mass greater than 1.0 cm after surgery were randomly assigned to receive cisplatin 75 mg/m2 plus a 24-hour infusion of paclitaxel 135 mg/m2 (arm I), or carboplatin area under the curve 7.5 intravenously plus paclitaxel 175 mg/m2 over 3 hours (arm II). RESULTS Seven hundred ninety-two eligible patients were enrolled onto the study. Prognostic factors were similar in the two treatment groups. Gastrointestinal, renal, and metabolic toxicity, as well as grade 4 leukopenia, were significantly more frequent in arm I. Grade 2 or greater thrombocytopenia was more common in arm II. Neurologic toxicity was similar in both regimens. Median progression-free survival and overall survival were 19.4 and 48.7 months, respectively, for arm I compared with 20.7 and 57.4 months, respectively, for arm II. The relative risk (RR) of progression for the carboplatin plus paclitaxel group was 0.88 (95% confidence interval [CI], 0.75 to 1.03) and the RR of death was 0.84 (95% CI, 0.70 to 1.02). CONCLUSION In patients with advanced ovarian cancer, a chemotherapy regimen consisting of carboplatin plus paclitaxel results in less toxicity, is easier to administer, and is not inferior, when compared with cisplatin plus paclitaxel.

Vascular endothelial growth factor (VEGF) expression and survival in human epithelial ovarian carcinomas

Vascular endothelial growth factor (VEGF) expression and microvessel density were studied in cases of advanced epithelial ovarian carcinoma to evaluate their usefulness as prognostic variables. Tumor samples from 18 patients with advanced stage serous epithelial ovarian cancer were evaluated for VEGF expression by reverse-transcriptase polymerase chain reaction (RT-PCR) analysis. Immunohistochemical study of corresponding archival tissues with an antibody to von Willebrand factor (vWF; FVIII-RA) was used for tumor microvessel count determinations. The correlation of VEGF expression and mean microvessel counts was determined by an unpaired t-test. Survival analysis for known prognostic factors and VEGF expression was performed. Survival distributions were calculated by the product limit of Kaplan and Meier and significant differences between distributions were analyzed with a log rank test. From the RT-PCR analysis of tumor VEGF expression, 12 samples were found to be strongly positive, whereas six samples had low/negative VEGF expression. The median survival was 60 months for the VEGF-low/negative group and 28 months for the VEGF-positive group (P = 0.058). Other prognostic variables had minimal impact on survival, i.e. age < 65 years (P = 0.873), FIGO stage (P = 0.06), grade (P = 0.236) and debulking status (P = 0.842). Fourteen of 18 tumor specimens were suitable for microvessel counting. The mean microvessel counts of the VEGF-positive group and the VEGF-negative group were 27/hpf and 35/hpf, respectively (P = 0.16). In this preliminary analysis, high VEGF expression in epithelial ovarian carcinomas was associated with poor overall survival. Further study will be necessary to elucidate the lack of association of VEGF expression and tumor microvessel counts.

Sunitinib malate in the treatment of recurrent or persistent uterine leiomyosarcoma: A Gynecologic Oncology Group phase II study

PURPOSE New agents are needed for patients with metastatic uterine leiomyosarcoma who progress after treatment with doxorubicin or gemcitabine-docetaxel. Agents targeting tumor vasculature have potential for activity in leiomyosarcoma. We aimed to assess the activity of sunitinib in patients with recurrent uterine leiomyosarcoma who had received one or two prior therapies by determining the frequency of patients who survived progression-free for at least 6 months or who achieved objective tumor response. We also aimed to characterize the toxicity of sunitinib and to estimate time-to-progression. PATIENTS AND METHODS Eligible patients with uterine leiomyosarcoma were treated with sunitinib 50 mg by mouth daily for 4 weeks, with 2 weeks rest. Tumor response and progression-free status were assessed every 6 weeks. RESULTS Twenty-three of 25 patients enrolled were evaluable for efficacy (two wrong histologies). The median number of cycles was one. Two of 23 patients achieved a partial response (8.7%, 90% two-sided, binomial confidence interval (CI) 1.6-24.9%). Four patients remained progression-free at 6 months (17.4%, 90% two-sided, binomial confidence interval 6.2-35.5%). Toxicities included: grade 3 neutropenia (17.4%); grade 3 thrombocytopenia (13%); grade 3 anemia (17.4%); grades 3-4 lymphopenia (8.7%); grades 3-4 fatigue (30%); grade 3 vomiting/diarrhea (21.7%); skin rash/hand-foot syndrome, grade 2 (13%), grade 3 (4.3%); hypertension, grade 2 (39%), grade 3 (4.3%); grade 2 decrease in cardiac ejection fraction (4.3%), and grade 3 thrombosis (4.3%) Median progression-free survival (PFS) was 1.5 months. CONCLUSION Sunitinib fails to achieve sufficient objective response or sustained disease stabilization as second- or third-line treatment for uterine leiomyosarcoma.

Trends in United States ovarian cancer mortality, 1979-1995

OBJECTIVE To describe the epidemiology of ovarian cancer mortality in the United States from 1979 to 1995. METHODS The mortality data of the Centers for Disease Control and Prevention were accessed using the Wide-ranging Online Data for Epidemiologic Research (WONDER). We selected all deaths among women with International Classification of Diseases, Ninth Revision (ICD-9) code 183.0 (ovarian malignant neoplasm). Mortality data for the years 1979-1995 were age-adjusted to the United States 1990 female population, and mortality rates for each year were calculated for females of all ages by age category, by race, and by geographic location. Trends were obtained for the periods 1979-1983 to 1991-1995, and the impact on the number of ovarian cancer deaths was calculated. RESULTS Age-adjusted ovarian cancer mortality rates have changed little in the United States from 1979 to 1995, but rates are increasing in older women (65 years and older) and decreasing in younger women. Age-adjusted mortality rates are higher among whites than in blacks. Ovarian cancer mortality rates are higher in northern compared with southern states. CONCLUSION The trends in ovarian cancer mortality among younger and older women parallel published changes in incidence and may be due to changes in risk factors, such as the use of oral contraceptives. The reasons for the higher ovarian cancer death rates in northern states are unknown. Better understanding of how modifiable risk factors and treatment methods affect ovarian cancer mortality trends is needed.

Frequency-dependent complex modulus of the uterus: preliminary results

The frequency-dependent complex moduli of human uterine tissue have been characterized. Quantification of the modulus is required for developing uterine ultrasound elastography as a viable imaging modality for diagnosing and monitoring causes for abnormal uterine bleeding and enlargement, as well assessing the integrity of uterine and cervical tissue. The complex modulus was measured in samples from hysterectomies of 24 patients ranging in age from 31 to 79 years. Measurements were done under small compressions of either 1 or 2%, at low pre-compression values (either 1 or 2%), and over a frequency range of 0.1-100 Hz. Modulus values of cervical tissue monotonically increased from approximately 30-90 kPa over the frequency range. Normal uterine tissue possessed modulus values over the same range, while leiomyomas, or uterine fibroids, exhibited values ranging from approximately 60-220 kPa.

A Protocol of Dual Prophylaxis for Venous Thromboembolism Prevention in Gynecologic Cancer Patients

OBJECTIVE: To evaluate a quality improvement protocol for venous thromboembolism prevention in postoperative gynecologic cancer patients. METHODS: On January 1, 2006, we initiated a universal protocol of dual prophylaxis with sequential compression devices and three times daily heparin (or daily low molecular weight heparin) until discharge in gynecologic cancer patients having major surgery. Patients with both malignancy and age over 60 years (or history of prior clot) were discharged on 2 weeks of anticoagulant. Before January 2006, all patients were given sequential compression devices starting before the induction of anesthesia, continuing until discharge from the hospital. Records of gynecologic cancer service patients admitted in 2005 and 2006 were reviewed, excluding patients with a history of heparin-induced thrombocytopenia or those admitted on an anticoagulant. Any pulmonary embolism or deep vein thrombosis diagnosed within 6 weeks of surgery was identified. We performed &khgr;2 and Wilcoxon rank sum tests as well as multivariable regression analysis for confounders. RESULTS: Six of the 311 women meeting inclusion criteria in 2006 (1.9%) and 19 of 294 (6.5%) in 2005 had venous thromboembolism (odds ratio 0.33, 95% confidence interval 0.12–0.88, multivariable analysis adjusting for baseline differences between the groups). Heparin was given to 98.1% of patients in the hospital in 2006, and 91.1% of those meeting high-risk criteria were discharged on an anticoagulant. No differences in major bleeding complications were seen between years. CONCLUSION: A protocol of dual prophylaxis with prolonged prophylaxis in high-risk patients was successfully implemented and was associated with a significant reduction in the rate of venous thromboembolism without increasing bleeding complications. LEVEL OF EVIDENCE: II

Preoperative hypoalbuminemia is an independent predictor of poor perioperative outcomes in women undergoing open surgery for gynecologic malignancies.

OBJECTIVE To quantify the impact of preoperative hypoalbuminemia on 30-day mortality and morbidity after gynecologic cancer surgery. METHODS Patients included in the National Surgical Quality Improvement Program (NSQIP) dataset who underwent any non-emergent surgery for gynecologic malignancy between 1/1/2008 and 12/31/2010 were identified. Analysis was conducted with albumin both as a dichotomous variable (<3.5 g/dl was defined as low albumin) and as a continuous variable to determine a clinically relevant cut-off value. RESULTS Of the total 3171 patients identified, 2110 had preoperative albumin levels available for analysis. In addition, 279 (13.3%) of these patients had low albumin levels. According to multivariate analysis, the low albumin group had significantly higher odds of developing one or more post-operative complications (OR-2,CI: 1.47-2.73, p<0.0001), three or more complications (OR-4.1,CI: 2.31-7.1, p<0.0001), surgical complications (OR-2.39,CI: 1.59-3.58, p<0.0001), thromboembolic complications (OR-2.59,CI: 1.33-5.06, p<0.0001), pulmonary complications (OR-4.06,CI: 2.05-8.03, p<0.0001), or infectious complications (OR-1.84,CI: 1.26-2.69, p<0.0001) and a higher 30-day mortality (OR-6.52,CI: 2.51-16.95, p<0.0001). Upon subgroup analysis, this difference was not found in patients undergoing laparoscopic surgery. In patients undergoing open surgery, the probability of experiencing one or more post-operative complications increased linearly with the decrease in albumin level; however, the probability of patients experiencing three or more complications and 30-day mortality increased sharply as soon as the albumin level decreased below 3g/dl. CONCLUSION Preoperative albumin levels <3g/dL identify a population of patients at a very high-risk of experiencing perioperative morbidity and 30-day mortality after open surgery.

Use of a bupivacaine continuous wound infusion system in gynecologic oncology: a randomized trial.

Objective: The aim of the current study was to evaluate the safety and efficacy of a widely available bupivacaine continuous wound infusion system in gynecologic oncology patients undergoing laparotomy. Methods: A prospective, randomized, double-blind, placebo-controlled trial was performed. After closure of the fascia, flexible soaker catheters were placed in the deep subcutaneous space. The infusion pump was filled with 290 mL of either 0.5% bupivacaine or normal saline, to infuse over 72 hours. Daily assessments of pain scores utilized the Wisconsin Brief Pain Inventory. All patients received intravenous narcotics via patient-controlled devices. Results: Eighty surgeries were evaluated in a total of 79 women (40 per arm). Mean age was 56 years, with 79% having invasive gynecologic pathology. The two groups were not significantly different in terms of type of surgery, length of incision, estimated blood loss, operative time, or medical history. Postoperative outcomes, including wound toxicity, time to flatus, and hospital stay, did not differ. Study patients averaged 75 mg intravenously and 107 mg total narcotic use (morphine equivalent), whereas controls averaged 60 mg intravenously and 86 mg total (P = .40 intravenously; P = .25 total). Acetaminophen and intravenous ketorolac consumption were equal between groups. The Brief Pain Inventory score for “current pain” was 2.84 for bupivacaine patients and 3.14 for controls (P = .46; least = 0, most = 10). There was no individual postoperative day when “current pain” BPI scores differed. “Worst pain” and “least pain” Brief Pain Inventory scores showed similar results. Conclusion: The results suggest that although the continuous infusion system seems safe, it is not efficacious in this patient population. Level of Evidence: I

Intensive postoperative glucose control reduces the surgical site infection rates in gynecologic oncology patients

OBJECTIVE SSI rates after gynecologic oncology surgery vary from 5% to 35%, but are up to 45% in patients with diabetes mellitus (DM). Strict postoperative glucose control by insulin infusion has been shown to lower morbidity, but not specifically SSI rates. Our project studied continuous postoperative insulin infusion for 24h for gynecologic oncology patients with DM and hyperglycemia with a target blood glucose of <139 mL/dL and a primary outcome of the protocols impact on SSI rates. METHODS We compared SSI rates retrospectively among three groups. Group 1 was composed of patients with DM whose blood glucose was controlled with intermittent subcutaneous insulin injections. Group 2 was composed of patients with DM and postoperative hyperglycemia whose blood glucose was controlled by insulin infusion. Group 3 was composed of patients with neither DM nor hyperglycemia. We controlled for all relevant factors associated with SSI. RESULTS We studied a total of 372 patients. Patients in Group 2 had an SSI rate of 26/135 (19%), similar to patients in Group 3 whose rate was 19/89 (21%). Both were significantly lower than the SSI rate (43/148, 29%) of patients in Group 1. This reduction of 35% is significant (p = 0.02). Multivariate analysis showed an odd ratio = 0.5 (0.28-0.91) in reducing SSI rates after instituting this protocol. CONCLUSIONS Initiating intensive glycemic control for 24h after gynecologic oncology surgery in patients with DM and postoperative hyperglycemia lowers the SSI rate by 35% (OR = 0.5) compared to patients receiving intermittent sliding scale insulin and to a rate equivalent to non-diabetics.

In Vitro Uterine Strain Imaging Preliminary Results

Uterine abnormalities, such as leiomyomas, endometrial polyps, and adenomyosis, are often clinically associated with irregular uterine bleeding. These abnormalities can have similar B‐mode characteristics but require different treatment. The objective of this study was to develop diagnostic techniques based on ultrasound strain imaging that would allow in vivo visualization and characterization of endometrial and myometrial uterine abnormalities, enabling physicians to improve diagnosis and treatment.