GOG 8020/210: Risk stratification of lymph node metastasis, disease progression and survival using single nucleotide polymorphisms in endometrial cancer: An NRG oncology/gynecologic oncology group study.

OBJECTIVES: The ability to stratify a patient's risk of metastasis and survival permits more refined care. A proof of principle study was undertaken to investigate the relationship between single nucleotide polymorphisms (SNPs) in literature based candidate cancer genes and the risk of nodal metastasis and clinical outcome in endometrioid endometrial cancer (EEC) patients. METHODS: Surgically-staged EEC patients from the Gynecologic Oncology Group or Washington University School of Medicine with germline DNA available were eligible. Fifty-four genes represented by 384 SNPs, were evaluated by Illumina Custom GoldenGate array. Association with lymph node metastases was the primary outcome. Progression-free survival (PFS) and overall survival (OS) was also evaluated. RESULTS: 361 SNPs with high quality genotype data were evaluated in 337 patients with outcome data. Five SNPs in CXCR2 had an odds ratio (OR) between 0.68 and 0.70 (p-value ≤ 0.025). The A allele rs946486 in ABL had an OR of 1.5 (p-value = 0.01) for metastasis. The G allele in rs7795743 in EGFR had an OR for metastasis of 0.68 (p-value = 0.02) and hazard ratio (HR) for progression of 0.66 (p-value = 0.004). Importantly, no SNP met genome wide significance after adjusting for multiple test correcting and clinical covariates. The A allele in rs2159359 SNP in NME1 and the G allele in rs13222385 in EGFR were associated with worse OS. Both exhibited genome wide significance; rs13222385 remained significant after adjusting for prognostic clinical variables. CONCLUSION: SNPs in cancer genes including rs2159359 SNP in NME1 and rs13222385 in EGFR may stratify risk in EEC and are prioritized for further investigation.

Clinicopathologic characteristics and survival of patients with gynecologic malignancies metastatic to the brain.

OBJECTIVE: No standardized treatment strategies exist for patients with gynecologic malignancies complicated by brain metastases. Identification of poor outcome characteristics, long-term survival indicators, and molecular markers could help individualize and optimize treatment. METHODS: This retrospective cohort study included 100 gynecologic cancer patients with brain metastases treated at our institution between January 1990 and June 2009. Primary outcome was overall survival (OS) from time of diagnosis of brain metastases. We used univariate and multivariate analyses to evaluate associations between OS and clinical factors. We used immunohistochemistry to examine expression of five molecular markers in primary tumors and brain metastases in a subset of patients and matched controls. Statistical tests included the Student's paired t-test (for marker expression) and Kaplan-Meier test (for correlations). RESULTS: On univariate analysis, primary ovarian disease, CA-125<81units/mL at brain metastases diagnosis, and isolated versus multi-focal metastases were all associated with longer survival. Isolated brain metastasis remained the only significant predictor on multivariate analysis (HR 2.66; CI 1.19-5.93; p=0.017). Expression of vascular endothelial growth factor A (VEGF-A) was higher in metastatic brain samples than in primary tumors of controls (p<0.0001). None of the molecular markers were significantly associated with survival. CONCLUSIONS: Multi-modality therapy may lead to improved clinical outcomes, and VEGF therapy should be investigated in treatment of brain metastases.

Chemotherapy Response Rates Among Patients With Endometrial Cancer Who Have Elevated Serum Platelets.

OBJECTIVE: This retrospective study evaluates the influence of serum platelet count on chemotherapy response rates among women with endometrial cancer. METHODS: From 3 separate cancer centers, a total of 318 patients with endometrial cancer who received postoperative chemotherapy between June 1999 and October 2009 were retrospectively identified. Endometrioid, serous, clear cell, and carcinosarcoma histologies were included. Patients were classified as having an elevated platelet count if their serum platelet count was greater than 400 × 109/L at the time of initial diagnosis. Primary outcome was chemotherapy response, classified as either complete or partial/refractory. Secondary outcomes were disease-free and disease-specific survival. χ² Test and Student t test were performed as appropriate. Kaplan-Meier curves and Cox proportional hazards models were used to assess serum platelet effect on survival. RESULTS: There were 125 deaths, 76 recurrences, and 48 disease progressions. Of the total group, 53 (16.7%) were categorized as having an elevated platelet count. An elevated platelet count was associated with a lower chemotherapy response rate in univariate analysis (hazard ratio [HR], 2.8; 95% 95% confidence interval [CI], 1.46-5.38; P < 0.01). Multivariate analysis showed elevated platelets to be independently associated with decreased disease-free survival (HR, 2.24; 95% CI, 1.26-3.98; P < 0.01) but not disease-specific survival (HR, 1.03; 95% CI, 0.56-1.88, P = 0.93). CONCLUSIONS: Patients with endometrial cancer who have an elevated serum platelet count greater than 400 × 109/L may have lower chemotherapy response rates and are at increased risk for recurrence when compared with patients with a count within the reference range.

A phase II trial of a surgical protocol to decrease the incidence of wound complications in obese gynecologic oncology patients.

OBJECTIVES: Obese women have a high incidence of wound separation after gynecologic surgery. We explored the effect of a prospective care pathway on the incidence of wound complications. METHODS: Women with a body mass index (BMI) ≥30 kg/m(2) undergoing a gynecologic procedure by a gynecologic oncologist via a vertical abdominal incision were eligible. The surgical protocol required: skin and subcutaneous tissues to be incised using a scalpel or cutting electrocautery, fascial closure using #1 polydioxanone suture, placement of a 7 mm Jackson-Pratt drain below Camper's fascia, closure of Camper's fascia with 3-0 plain catgut suture and skin closure with staples. Wound complication was defined as the presence of either a wound infection or any separation. Demographic and perioperative data were analyzed using contingency tables. Univariable and multivariable regression models were used to identify predictors of wound complications. Patients were compared using a multivariable model to a historical group of obese patients to assess the efficacy of the care pathway. RESULTS: 105 women were enrolled with a median BMI of 38.1. Overall, 39 (37%) had a wound complication. Women with a BMI of 30-39.9 kg/m(2) had a significantly lower risk of wound complication as compared to those with a BMI >40 kg/m(2) (23% vs 59%, p<0.001). After controlling for factors associated with wound complications the prospective care pathway was associated with a significantly decreased wound complication rate in women with BMI <40 kg/m(2) (OR 0.40, 95% C.I.: 0.18-0.89). CONCLUSION: This surgical protocol leads to a decreased rate of wound complications among women with a BMI of 30-39.9 kg/m(2).

A randomized trial of buffered versus nonbuffered lidocaine with epinephrine for cervical loop excision.

OBJECTIVE: Our study evaluated whether buffering reduces pain from lidocaine injection for loop electrosurgical excisional procedures (LEEPs) of the cervix when compared to unbuffered lidocaine. METHODS: Women undergoing outpatient LEEPs were randomized to receive either buffered or unbuffered lidocaine. Participants, caregivers, and statisticians were blinded to treatment allocation. Pain was categorized as injection, procedure, or cramping pain. Severity of pain was reported using a Likert visual analog scale and compared using Mann-Whitney tests. RESULTS: Twenty-eight subjects received buffered lidocaine and 24 subjects received unbuffered lidocaine. The 2 groups were similar in regard to age, race, previous LEEP, anesthetic volume used, and loop size. Mean scores were similar between the nonbuffered and buffered groups for injection pain (25 vs 19, p = .13), procedure pain (27 vs 19, p = .08), and cramping pain (19 vs 18, p = .86). CONCLUSIONS: Pain scores with subepithelial lidocaine plus epinephrine for LEEP are low and are not significantly reduced by buffering the anesthetic.

Glycogen synthase kinase 3ß inhibition as a therapeutic approach in the treatment of endometrial cancer.

Alternative strategies beyond current chemotherapy and radiation therapy regimens are needed in the treatment of advanced stage and recurrent endometrial cancers. There is considerable promise for biologic agents targeting the extracellular signal-regulated kinase (ERK) pathway for treatment of these cancers. Many downstream substrates of the ERK signaling pathway, such as glycogen synthase kinase 3ß (GSK3ß), and their roles in endometrial carcinogenesis have not yet been investigated. In this study, we tested the importance of GSK3ß inhibition in endometrial cancer cell lines and in vivo models. Inhibition of GSK3ß by either lithium chloride (LiCl) or specific GSK3ß inhibitor VIII showed cytostatic and cytotoxic effects on multiple endometrial cancer cell lines, with little effect on the immortalized normal endometrial cell line. Flow cytometry and immunofluorescence revealed a G2/M cell cycle arrest in both type I (AN3CA, KLE, and RL952) and type II (ARK1) endometrial cancer cell lines. In addition, LiCl pre-treatment sensitized AN3CA cells to the chemotherapy agent paclitaxel. Administration of LiCl to AN3CA tumor-bearing mice resulted in partial or complete regression of some tumors. Thus, GSK3ß activity is associated with endometrial cancer tumorigenesis and its pharmacologic inhibition reduces cell proliferation and tumor growth.

Uterine serous carcinoma: increased familial risk for lynch-associated malignancies.

Serous uterine cancer is not a feature of any known hereditary cancer syndrome. This study evaluated familial risk of cancers for patients with serous uterine carcinoma, focusing on Lynch syndrome malignancies. Fifty serous or mixed serous endometrial carcinoma cases were prospectively enrolled. Pedigrees were developed for 29 probands and tumors were assessed for DNA mismatch repair (MMR) abnormalities. Standardized incidence ratios for cancers in relatives were estimated. A second-stage analysis was undertaken using data from Gynecologic Oncology Group (GOG)-210. Incidence data for cancers reported in relatives of 348 patients with serous and mixed epithelial and 624 patients with endometrioid carcinoma were compared. Nineteen of 29 (65.5%) patients in the single-institution series reported a Lynch-related cancer in relatives. Endometrial and ovarian cancers were significantly overrepresented and a high number of probands (6 of 29, 20.7%) reported pancreatic cancers. None of the probands' tumors had DNA MMR abnormalities. There was no difference in endometrial or ovarian cancer incidence in relatives of serous and endometrioid cancer probands in the case-control study. Pancreatic cancers were, however, significantly more common in relatives of patients with serous cancer [OR, 2.39; 95% confidence interval (CI), 1.06-5.38]. We identified an excess of endometrial, ovarian, and pancreatic cancers in relatives of patients with serous cancer in a single-institution study. Follow-up studies suggest that only pancreatic cancers are overrepresented in relatives. DNA MMR defects in familial clustering of pancreatic and other Lynch-associated malignancies are unlikely. The excess of pancreatic cancers in relatives may reflect an as yet unidentified hereditary syndrome that includes uterine serous cancers.

Lymphovascular space invasion is an independent risk factor for nodal disease and poor outcomes in endometrioid endometrial cancer.

OBJECTIVE: Adjuvant radiotherapy improves local control but not survival in women with endometrial cancer. This benefit was shown in staged patients with "high intermediate risk" (HIR) disease. Other studies have challenged the need for systematic staging including lymphadenectomy. We sought to determine whether LVSI alone or in combination with other histologic factors predicts lymph node (LN) metastasis in patients with endometrioid endometrial cancer. METHODS: A retrospective review was conducted of patients with endometrioid endometrial carcinoma who had confirmed presence/absence of LVSI and clinicopathologic data necessary to identify HIR criteria. Kaplan-Meier curves were generated and univariate and multivariate analyses performed as appropriate. RESULTS: We identified 757 eligible patients and 628 underwent systematic lymphadenectomy for staging purposes. In the surgically staged group, 242 (38%) patients met uterine HIR criteria and 196 (31%) had LVSI. Both HIR and LVSI were significantly associated with LN metastasis. Among the HIR positive group, 59 had LN metastasis (OR 4.46, 95% CI 2.72-7.32, P<0.0001). Sixty-six LVSI positive patients had nodal metastasis (OR 11.04, 95% CI 6.39-19.07, P<0.0001). The NPV of LVSI and HIR negative specimens was 95.6% and 93.4% respectively. In multivariate analysis, PFS and OS were significantly reduced in both LVSI positive (P<0.0001) and HIR patients (P<0.0001) when compared to patients who were LVSI and HIR negative. CONCLUSIONS: HIR status and LVSI are highly associated with LN metastasis. These features are useful in assessing risk of metastatic disease and may serve as a surrogate for prediction of extrauterine disease.

Surgery in the pregnant patient.

The key pregnancy-related physiological maternal and fetal changes that occur and the modifications to standard surgical approaches that can impact surgical outcomes are important to recognize. Surgery during pregnancy can be safe and effective. Laparoscopy has become an acceptable alternative to the standard laparotomy and should be considered when surgeons with appropriate skills and experience are available. Care of these patients should always involve a multidisciplinary team with the goal to optimize outcomes for both the mother and the fetus.

The effects of body mass index on complications and survival outcomes in patients with cervical carcinoma undergoing curative chemoradiation therapy.

BACKGROUND: The effect of body mass index (BMI) on treatment outcomes for patients with locally advanced cervical carcinoma who receive definitive chemoradiation is unclear. METHODS: The cohort in this study included all patients with cervical carcinoma (n = 404) who had stage IB(1) disease and positive lymph nodes or stage ≥IB(2) disease and received treatment at the authors' facility between January 1998 and January 2008. The mean follow-up was 47.2 months. BMI was calculated using the National Institute of Health online calculator. BMI categories were created according to the World Health Organization classification system. Primary outcomes were overall survival, disease-free survival, and complication rate. Univariate and multivariate analyses were performed. Kaplan-Meier survival curves were generated and compared using Cox proportional hazard models. RESULTS: On multivariate analysis, compared with normal weight (BMI 18.5-24.9 kg/m(2) ), a BMI <18.5 kg/m(2) was associated with decreased overall survival (hazard ratio, 2.37; 95% confidence interval, 1.28-4.38; P < .01). The 5-year overall survival rate was 33%, 60%, and 68% for a of BMI <18.5 kg/m(2) , a BMI from 18.5 kg/m(2) to 24.9 kg/m(2) , and a BMI >24.9 kg/m(2) , respectively. A BMI <18.5 kg/m(2) was associated with increased risk of grade 3 or 4 complications compared with a BMI >24.9 kg/m(2) (radiation enteritis: 16.7% vs 13.6%, respectively; P = .03; fistula: 11.1% vs 8.8%, respectively; P = .05; bowel obstruction: 33.3% vs 4.4%, respectively; P < .001; lymphedema: 5.6% vs 1.2%, respectively; P = .02). CONCLUSIONS: Underweight patients (BMI <18.5 kg/m(2) ) with locally advanced cervical cancer had diminished overall survival and more complications than normal weight and obese patients.

Lower uterine segment involvement is associated with poor outcomes in early-stage endometrioid endometrial carcinoma.

BACKGROUND: The clinicopathologic significance of lower uterine segment involvement (LUSI) in endometrial cancer patients remains unclear. Although LUSI has been reported to be a prognostic indicator, literature is limited. METHODS: We studied 481 surgically staged endometrioid endometrial cancers with disease confined to the uterus (FIGO 1988 stage I or II). Primary outcomes were overall survival (OS) and disease-free survival (DFS). The relationships between LUSI and OS and DFS were assessed using the Kaplan-Meier method and Cox proportional hazard models. The t test or Fisher exact test was used for evaluating relationships between variables of interest. RESULTS: LUSI was present in 223 cases (46.4%), and was associated with both decreased disease free survival (P = 0.02) and overall survival (P = 0.01) in univariate analysis. Multivariate analysis confirmed the association between LUSI and increased risk for recurrence [hazard ratio (HR) 2.27; 95% confidence interval (95% CI) 1.09-4.7; P = 0.03] and increased mortality (HR 1.76; 95% CI 1.12-2.78; P = 0.01). CONCLUSIONS: LUSI in patients with early-stage endometrioid endometrial cancer is associated with decreased survival.

The role of neoadjuvant chemotherapy in the management of patients with advanced stage ovarian cancer: survey results from members of the Society of Gynecologic Oncologists.

OBJECTIVE: Recent randomized controlled data suggest that neoadjuvant chemotherapy (NACT) with interval debulking (ID) may produce similar overall survival and progression free survival compared to standard primary cytoreduction followed by chemotherapy. The object of our study was to assess current patterns of care among members of the Society of Gynecologic Oncologists (SGO), specifically collating their opinions on and use of NACT for advanced stage ovarian cancer. METHODS: A 20-item questionnaire was sent to all working e-mail addresses of SGO members (n=1137). The data was collected and analyzed using descriptive statistics with commercially available online survey software. The Chi-square test for independence was used to determine differences in responses between groups. RESULTS: Of 339 (30%) responding members, most rarely employ NACT, with 60% of respondents using NACT in less than 10% of advanced stage ovarian cancer cases. Respondents did not consider available evidence sufficient to justify NACT followed by ID (82%), nor did most think it should be preferred (74%). Sixty-two percent of respondents thought it was impossible to accurately predict preoperatively whether an optimal cytoreduction is possible. Thirty-nine percent believed that women with bulky upper abdominal disease on preoperative imaging would benefit from NACT versus primary debulking. If gross disease were found at ID, 43% would continue to treat with IV chemotherapy, and 42% would place an IP port if optimally cytoreduced. When ID reveals microscopic disease, 51% would continue IV treatment and the remaining IP therapy. Eighty-six percent of the respondents believed that both biological and surgical factors determine patient outcomes. CONCLUSIONS: The majority of responding SGO members do not treat patients with NACT followed by ID. Currently available studies of NACT/ID have been insufficient to convince most gynecologic oncologists to incorporate it into practice. Our results provide a benchmark against which further research can assess the penetration of NACT/ID into clinical practice.

The role of PET/CT in the management of patients with cervical cancer: practice patterns of the members of the Society of Gynecologic Oncologists.

OBJECTIVES: Recent data has highlighted the role of PET/CT in the pretreatment evaluation and follow-up of patients with cervical cancer. The objective of our study was to assess the acceptance of PET/CT into the management of patients with cervical cancer. We also explored potential barriers to the use of these imaging modalities in patients with cervical cancer. METHODS: A 14-item electronic questionnaire was initially sent to all working addresses of members of the SGO (n=1048). An opt-out option was offered. For members who did not respond within 3 weeks, a second electronic invitation was sent. A third request was finally sent to further improve response rates. Data were collected and analyzed using a commercially available on-line survey database. RESULTS: A total of 305 responses were collected for an overall 30% response rate. PET/CT appears to be widely available (99%) and accessible (75%) in most practices. Although 83% of members order routine CT imaging for all newly diagnosed cervical cancer cases, only 28% routinely order a PET/CT. Conversely, 64% would order a PET/CT for newly diagnosed patients with advanced disease or those at high risk for distant metastatic disease. Most members (82%) do not routinely use PET/CT to assess response to treatment. Twenty percent of members believe that no useful prognostic information can be obtained from routine use of molecular imaging in patients with cervical cancer. The most common barriers for use of PET/CT cited by members were perceived lack of third-party payer coverage and lack of scientific evidence. CONCLUSIONS: Despite clear scientific data supporting the use of PET/CT in patients with cervical cancer and apparent widespread availability, this imaging modality remains highly underutilized in clinical practice. Clarifying insurance coverage early in the evaluation process and replicating studies that have shown effectiveness of PET/CT in multiple roles may improve adoption of this potentially useful imaging modality.