Gretchen Glaser

A Phase II Study of Gemcitabine in Combination with Tanespimycin in Advanced Epithelial Ovarian and Primary Peritoneal Carcinoma

OBJECTIVE To evaluate the efficacy and biological effects of the gemcitabine/tanespimycin combination in patients with advanced ovarian and peritoneal cancer. To assess the effect of tanespimycin on tumor cells, levels of the chaperone proteins HSP90 and HSP70 were examined in peripheral blood mononuclear cells (PBMC) and paired tumor biopsy lysates. METHODS Two-cohort phase II clinical trial. Patients were grouped according to prior gemcitabine therapy. All participants received tanespimycin 154 mg/m(2) on days 1 and 9 of cycle 1 and days 2 and 9 of subsequent cycles. Patients also received gemcitabine 750 mg/m(2) on day 8 of the first treatment cycle and days 1 and 8 of subsequent cycles. RESULTS The tanespimycin/gemcitabine combination induced a partial response in 1 gemcitabine naïve patient and no partial responses in gemcitabine resistant patients. Stable disease was seen in 6 patients (2 gemcitabine naïve and 4 gemcitabine resistant). The most common toxicities were hematologic (anemia and neutropenia) as well as nausea and vomiting. Immunoblotting demonstrated limited upregulation of HSP70 but little or no change in levels of most client proteins in PBMC and paired tumor samples. CONCLUSIONS Although well tolerated, the tanespimycin/gemcitabine combination exhibited limited anticancer activity in patients with advanced epithelial ovarian and primary peritoneal carcinoma, perhaps because of failure to significantly downregulate the client proteins at clinically achievable exposures.

The use of CT findings to predict extent of tumor at primary surgery for ovarian cancer

BACKGROUND High tumor dissemination (HTD) is a major risk factor for serious morbidity after primary ovarian cancer (OC) surgery, particularly in medically compromised patients. We performed a pilot study of whether CT findings could predict extent of disease and surgical complexity necessary in advanced OC. METHODS Preoperative CT images for patients with advanced OC from 1997-2003 were evaluated for rigorously defined disease-related findings and compared to both the findings at exploration and the required surgical procedures. Associations were assessed by the chi-square test. RESULTS Forty-six cases met inclusion criteria. Mean age was 66.4y, and 76% had residual disease (RD) 1cm or less. CT and surgical findings correlated (sensitivity/specificity) as follows: diaphragm disease (48%/100%); surface liver (100%/93%); omental cake (72%/65%); any sigmoid involvement (54%/100%); ascites (44%/100%); extra-pelvic large bowel involvement (29%/91%). When diaphragm disease and omental cake were present, HTD was found in all cases (positive predictive value and specificity=100%, sensitivity 48%). For CT findings of liver, large bowel and spleen involvement there was a strong trend toward resection (P=0.001, P=0.06 and P=0.06, respectively). CONCLUSIONS The findings of diaphragm disease and omental cake on CT scan are highly predictive for high tumor dissemination (HTD) and thus likelihood of extensive surgery required to achieve low residual disease. In addition, multiple CT findings correlate strongly with the need for higher surgical complexity which should facilitate preoperative planning and/or triage to specialized centers. These preliminary data suggest specific CT findings can be used to optimize treatment planning.

Conventional Chemotherapy and Oncogenic Pathway Targeting in Ovarian Carcinosarcoma Using a Patient-Derived Tumorgraft

Ovarian carcinosarcoma is a rare subtype of ovarian cancer with poor clinical outcomes. The low incidence of this disease makes accrual to large clinical trials challenging. However, studies have shown that treatment responses in patient-derived xenograft (PDX) models correlate with matched-patient responses in the clinic, supporting their use for preclinical testing of standard and novel therapies. An ovarian carcinosarcoma PDX is presented herein and showed resistance to carboplatin and paclitaxel (similar to the patient) but exhibited significant sensitivity to ifosfamide and paclitaxel. The PDX demonstrated overexpression of EGFR mRNA and gene amplification by array comparative genomic hybridization (log2 ratio 0.399). EGFR phosphorylation was also detected. Angiogensis and insulin-like growth factor pathways were also implicated by overexpression of VEGFC and IRS1. In order to improve response to chemotherapy, the PDX was treated with carboplatin/paclitaxel with or without a pan-HER and VEGF inhibitor (BMS-690514) but there was no tumor growth inhibition or improved animal survival, which may be explained by a KRAS mutation. Resistance was also observed when the IGF-1R inhibitor BMS-754807 was combined with carboplatin/paclitaxel. Because poly (ADP-ribose) polymerase inhibitors have activity in ovarian cancer patients, with and without BRCA mutations, ABT-888 was also tested but found to have no activity. Pathogenic mutations were also detected in TP53 and PIK3CA. In conclusion, ifosfamide/paclitaxel was superior to carboplatin/paclitaxel in this ovarian carcinosarcoma PDX and gene overexpression or amplification alone was not sufficient to predict response to targeted therapy. Better predictive markers of response are needed.

Mutations in homologous recombination genes and outcomes in ovarian carcinoma patients in GOG 218: An NRG oncology/Gynecologic oncology group study

Purpose: We hypothesized that mutations in homologous recombination repair (HRR) genes beyond BRCA1 and BRCA2 improve outcomes for ovarian carcinoma patients treated with platinum therapy and would impact the relative benefit of adding prolonged bevacizumab. Experimental Design: We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced ovarian carcinoma of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes. Proportional hazards models were used to estimate relative hazards for progression-free survival (PFS) and overall survival (OS). Results: Of 1,195 women with ovarian carcinoma, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared with those without mutations were lower for women with non-BRCA HRR mutations [HR = 0.73; 95% confidence interval (CI), 0.57–0.94; P = 0.01 for PFS; HR = 0.67; 95% CI, 0.50–0.90; P = 0.007 for OS] and BRCA1 mutations (HR = 0.80; 95% CI, 0.66–0.97; P = 0.02 for PFS; HR = 0.74; 95% CI, 0.59–0.94; P = 0.01 for OS) and were lowest for BRCA2 mutations (HR = 0.52; 95% CI, 0.40–0.67; P < 0.0001 for PFS; HR = 0.36; 95% CI, 0.25–0.53; P < 0.0001 for OS). A test of interaction showed no difference in the effect of bevacizumab on PFS between cases with and without mutations. Conclusions: HRR mutations, including non-BRCA genes, significantly prolong PFS and OS in ovarian carcinoma and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status. Clin Cancer Res; 24(4); 777–83. ©2017 AACR.

Clinical Utility of Preoperative Computed Tomography in Patients With Endometrial Cancer

Objective The aim of this study was to determine the clinical utility of routine preoperative pelvic and abdominal computed tomography (CT) examinations in patients with endometrial cancer (EC). Methods We retrospectively reviewed records from patients with EC who underwent a preoperative endometrial biopsy and had surgery at our institution from January 1999 through December 2008. In the subset with an abdominal CT scan obtained within 3 months before surgery, we evaluated the clinical utility of the CT scan. Results Overall, 224 patients (18%) had a preoperative endometrial biopsy and an available CT scan. Gross intra-abdominal disease was observed in 10% and 20% of patients with preoperative diagnosis of endometrioid G3 and type II EC, respectively, whereas less than 5% of patients had a preoperative diagnosis of hyperplasia or low-grade EC. When examining retroperitoneal findings, we observed that a negative CT scan of the pelvis did not exclude the presence of pelvic node metastasis. Alternately, a negative CT scan in the para-aortic area generally reduced the probability of finding para-aortic dissemination but with an overall low sensitivity (42%). However, the sensitivity for para-aortic dissemination was as high as 67% in patients with G3 endometrioid cancer. In the case of negative para-aortic nodes in the CT scan, the risk of para-aortic node metastases decreased from 18.8% to 7.5% in patients with endometrioid G3 EC. Up to 15% of patients with endometrioid G3 cancer had clinically relevant incidental findings that necessitated medical or surgical intervention. Conclusions In patients with endometrioid G3 and type II EC diagnosed by the preoperative biopsy, CT scans may help guide the operative plan by facilitating preoperative identification of gross intra-abdominal disease and enlarged positive para-aortic nodes that are not detectable during physical examinations. In addition, CT may reveal other clinically relevant incidental findings.

Impact of Sentinel Node Approach in Gynecologic Cancer on Training Needs

STUDY OBJECTIVE We sought to estimate the impact of sentinel nodes in gynecologic oncology on fellowship training and discuss potential solutions. DESIGN Retrospective multi-institution cohort (Canadian Task Force classification II-2). SETTING Three tertiary cancer referral cancer centers. PATIENTS Patients with endometrial and vulvar cancer undergoing lymph node evaluation. INTERVENTIONS Patient history and fellow case volumes were evaluated retrospectively for type of lymph node assessment. MEASUREMENTS AND MAIN RESULTS Minimally invasive endometrial cancer and vulvar cancer fellow case volumes in 3 large institutions were reviewed and average annual volumes calculated for each clinical gynecologic oncology fellow. For vulvar cancer, probabilities of sentinel lymph node mapping and laterality of lesions were estimated from the literature. For endometrial cancer, estimates of lymphadenectomy rates were determined using probabilities calculated from our historic database and from review of the literature. Modeling the approaches to lymphadenectomy in endometrial cancer (full, selective, and sentinel), 100% versus 68% versus 24%, respectively, of patients would require complete pelvic lymphadenectomy and 100% versus 34% versus 12% would require para-aortic lymphadenectomy. In vulvar cancer, rates of inguinal femoral lymphadenectomy are expected to drop from 81% of unilateral groins to only 12% of groins. CONCLUSIONS Sentinel lymph node biopsy for endometrial and vulvar cancer will play an increasing role in practice, and coincident with this will be a dramatic decrease in pelvic, para-aortic, and inguinal femoral lymphadenectomies. The declining numbers will require new strategies to maintain competency in our specialty. New approaches to surgical training and continued medical education will be necessary to ensure adequate training for fellows and young faculty across gynecologic surgery.

Enhanced Recovery Following Minimally Invasive Gynecologic Procedures with Bowel Surgery: A Systematic Review

Enhanced recovery after surgery (ERAS) is an evidence-based approach to perioperative care of the surgical patient. A mounting body of literature in gynecologic surgery has demonstrated that ERAS improves postoperative outcomes, shortens hospital length of stay, and reduces cost without increasing complications or readmissions. Most of the existing literature has concentrated on open surgery, questioning if patients undergoing minimally invasive surgery also derive benefit. Our aim was to systematically review the literature on ERAS after minimally invasive gynecologic surgery (MIGS) with and without bowel surgery. Given the paucity of studies on ERAS in MIGS with bowel surgery (1 study), we expanded our search to include studies of ERAS in patients undergoing minimally invasive colorectal resections alone. Twelve studies were identified through an electronic database search of PubMed, Medline, and Ovid EMBASE. These studies included patients undergoing MIGS for benign and/or malignant indications and showed that ERAS pathways decreased length of stay and/or increased the proportion of same-day discharge surgeries, improved patient satisfaction, and reduced hospital costs while maintaining low postoperative complication and readmission rates. Although limited, data from a single study suggest that ERAS in MIGS with bowel surgery leads to shortened hospital stay, stable postoperative morbidity, and less readmissions. Although the variation between the published protocols underscores the need for standardization, existing literature supports the adoption of ERAS as safe and effective when planning MIGS.

Adequate pelvic lymphadenectomy and survival of women with early-stage epithelial ovarian cancer

Objective To examine the trends and survival for women with early-stage epithelial ovarian cancer who underwent adequate lymphadenectomy during surgical treatment. Methods This is a retrospective observational study examining the Surveillance, Epidemiology, End Results program between 1988 and 2013. We evaluated 21,537 cases of stage I–II epithelial ovarian cancer including serous (n=7,466), clear cell (n=6,903), mucinous (n=4,066), and endometrioid (n=3,102) histology. A time-trend analysis of the proportion of patients who underwent adequate pelvic lymphadenectomy (≥8 per Gynecologic Oncology Group [GOG] criteria, ≥12 per Collaborative Group Report [CGR] criteria for bladder cancer, and >22 per Mayo criteria for endometrial cancer) and a survival analysis associated with adequate pelvic lymphadenectomy were performed. Results There were significant increases in the proportion of women who underwent adequate lymphadenectomy: GOG criteria 3.6% to 28.6% (1988–2010); CGR criteria 2.4% to 22.4% (1988–2013); and Mayo criteria 0.7% to 9.5% (1988–2013) (all, p<0.05). On multivariable analysis, adequate lymphadenectomy was independently associated with improved cause-specific survival compared to inadequate lymphadenectomy: GOG criteria, adjusted-hazard ratio (HR)=0.75, CGR criteria, adjusted-HR=0.77, and Mayo criteria, adjusted-HR=0.85 (all, p<0.05). Compared to inadequate lymphadenectomy, adequate lymphadenectomy was significantly associated with improved cause-specific survival for serous (HR range=0.67–0.73), endometrioid (HR range=0.59–0.61), and clear cell types (HR range=0.66–0.73) (all, p<0.05) but not in mucinous type (HR range=0.80–0.91; p>0.05). Conclusion Quality of lymphadenectomy during the surgical treatment for early-stage epithelial ovarian cancer has significantly improved. Adequate lymphadenectomy is associated with a 15%–25% reduction in ovarian cancer mortality compared to inadequate lymphadenectomy.

Enhanced recovery after surgery in gynecologic oncology

Enhanced recovery protocols consist of a bundle of concepts including early feeding, opioid‐sparing multimodal pain management, and euvolemia, with the overarching goal of hastening postoperative recovery. Enhanced recovery after surgery has been shown to reduce hospital length of stay, reduce costs, and decrease perioperative opioid requirements in benign and oncologic gynecologic surgery. Interventions without supporting evidence of benefit, such as the use of mechanical bowel preparation, routine use of nasogastric tubes and surgical drains, caloric restriction, routine use of intravenous opioid analgesics, and over‐vigorous intravenous hydration should be discouraged to improve broader endpoints such as patient satisfaction and overall recovery. Successful implementation requires engagement from a multidisciplinary team including surgeons, anesthesiologists, nurses, and pharmacists.

Frozen Section to Detect Empty Nodes and Improve the Accuracy of the Sentinel Lymph Node Biopsy in Endometrial Cancer

Sentinel lymph node (SLN) biopsy, identified after cervical injection of indocyanine green, has been proposed as an alternative to pelvic lymphadenectomy to reduce morbidity, operative time, and lymphatic-related complications for patients undergoing surgery for apparent staging of early-stage endometrial cancer. By identifying the presence or absence of lymph node metastasis at final pathology, SLN biopsy potentially reduces the need for intraoperative frozen section (FS). However, as recently reported by a single-institution case report, approximately 7% of all SLN biopsies do not show any lymph node at final pathology, actually representing what we called the ‘‘empty node’’ (EN). In our study, we estimated the rate of EN identified at FS in a large series of SLN biopsies for endometrial cancer staging and sought to determine the impact at a national level of routinely performing FS in the SLN removed.