Leigh A. Cantrell

A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study

BACKGROUND Sentinel-lymph-node mapping has been advocated as an alternative staging technique for endometrial cancer. The aim of this study was to measure the sensitivity and negative predictive value of sentinel-lymph-node mapping compared with the gold standard of complete lymphadenectomy in detecting metastatic disease for endometrial cancer. METHODS In the FIRES multicentre, prospective, cohort study patients with clinical stage 1 endometrial cancer of all histologies and grades undergoing robotic staging were eligible for study inclusion. Patients received a standardised cervical injection of indocyanine green and sentinel-lymph-node mapping followed by pelvic lymphadenectomy with or without para-aortic lymphadenectomy. 18 surgeons from ten centres (tertiary academic and community non-academic) in the USA participated in the trial. Negative sentinel lymph nodes (by haematoxylin and eosin staining on sections) were ultra-staged with immunohistochemistry for cytokeratin. The primary endpoint, sensitivity of the sentinel-lymph-node-based detection of metastatic disease, was defined as the proportion of patients with node-positive disease with successful sentinel-lymph-node mapping who had metastatic disease correctly identified in the sentinel lymph node. Patients who had mapping of at least one sentinel lymph node were included in the primary analysis (per protocol). All patients who received study intervention (injection of dye), regardless of mapping result, were included as part of the assessment of mapping and in the safety analysis in an intention-to-treat manner. The trial was registered with ClinicalTrials.gov, number NCT01673022 and is completed and closed. FINDINGS Between Aug 1, 2012, and Oct 20, 2015, 385 patients were enrolled. Sentinel-lymph-node mapping with complete pelvic lymphadenectomy was done in 340 patients and para-aortic lymphadenectomy was done in 196 (58%) of these patients. 293 (86%) patients had successful mapping of at least one sentinel lymph node. 41 (12%) patients had positive nodes, 36 of whom had at least one mapped sentinel lymph node. Nodal metastases were identified in the sentinel lymph nodes of 35 (97%) of these 36 patients, yielding a sensitivity to detect node-positive disease of 97·2% (95% CI 85·0-100), and a negative predictive value of 99·6% (97·9-100). The most common grade 3-4 adverse events or serious adverse events were postoperative neurological disorders (4 patients) and postoperative respiratory distress or failure (4 patients). 22 patients had serious adverse events, with one related to the study intervention: a ureteral injury incurred during sentinel-lymph-node dissection. INTERPRETATION Sentinel lymph nodes identified with indocyanine green have a high degree of diagnostic accuracy in detecting endometrial cancer metastases and can safely replace lymphadenectomy in the staging of endometrial cancer. Sentinel lymph node biopsy will not identify metastases in 3% of patients with node-positive disease, but has the potential to expose fewer patients to the morbidity of a complete lymphadenectomy. FUNDING Indiana University Health, Indiana University Health Simon Cancer Center, and the Indiana University Department of Obstetrics and Gynecology.

Frailty: An outcome predictor for elderly gynecologic oncology patients☆

OBJECTIVES The objective of this pilot study was to determine if frailty predicts surgical complications among elderly women undergoing gynecologic oncology procedures. METHODS A cohort of gynecologic oncology patients age ≥ 65, undergoing surgery between March and December 2011 was identified. Frailty was evaluated using a validated assessment tool. The primary outcome measure was 30 day postoperative complication rate. RESULTS Forty women were approached for study entry and 37 (92%) enrolled. The mean age was 73 years (range 65-95). The majority of women had a malignancy and underwent a major abdominal surgical procedure. Twenty-one women (57%) were not frail, 10 (27%) were intermediately frail and 6 (16%) were frail. There was no difference in age or prevalence of medical comorbidities between groups. Frail women had a significantly higher BMI compared to intermediately frail and not frail women, (36.0, 31.5 and 26.1 kg/m(2), p=0.02). The rate of 30-day surgical complications increased with frailty score and was 24%, versus 67% for women who were not frail as compared to the frail (p=0.04). CONCLUSIONS Pre-operative frailty assessment is well accepted by gynecologic oncology patients and feasible in a clinic setting. Frail women had a higher BMI, indicating that low body weight is not a marker for frailty, and had a significantly higher rate of 30-day postoperative complications in this pilot study. Initial findings support the concept of measuring frailty as a possible predictor for postoperative morbidity that will allow for improved patient counseling and decision making.

Retrospective review of an intraoperative algorithm to predict lymph node metastasis in low-grade endometrial adenocarcinoma

OBJECTIVE To validate the Mayo algorithm to intraoperatively identify women with endometrial cancer in whom lymphadenectomy may be safely omitted. METHODS A multi-center retrospective chart review 1977-2010 was completed using two independent institutional endometrial cancer databases. Eligibility criteria were grade 1 or 2 endometrial carcinoma, low-risk histology, and myometrial invasion ≤ 50% on intraoperative pathology consultation; patients were considered to satisfy the Mayo criteria if, in addition to these, tumor diameter on the final pathology report was ≤ 2 cm. Analysis of nodal metastases, recurrent disease, and progression-free survival (PFS) using the Kaplan-Meier method was performed. RESULTS Six hundred and two patients met inclusion criteria for the study. Of 110 patients satisfying the Mayo algorithm with an adequate lymphadenectomy, 2 (1.8%) were diagnosed with lymph node metastasis and 4 (3.6%) subsequently developed recurrent disease. The Mayo algorithm identified with a 98.2% negative predictive value women who would not benefit from a lymphadenectomy. There was no significant difference in recurrence rate or PFS between women who underwent lymphadenectomy and those who did not when the Mayo algorithm was satisfied. CONCLUSIONS The Mayo algorithm intraoperatively identifies tumor characteristics of low-risk disease in endometrial carcinoma that predict a very low likelihood of nodal metastasis and recurrence. Although a small number of patients with advanced stage disease may be missed when applying the Mayo criteria, there is no apparent survival benefit to lymphadenectomy for patients satisfying this algorithm, and these data support its use at other institutions.

Uterine carcinosarcoma: A review of the literature

OBJECTIVE Uterine carcinosarcomas (UCSs) are aggressive tumors previously considered to be sarcomas, but now recognized as malignancies composed of metaplastic transformation of epithelial elements. Much of the management for UCS has been extrapolated from studies of endometrial carcinomas and sarcomas. This article critically reviews the literature pertinent to the pathology, pathogenesis, diagnosis and management of women with UCS. METHODS MEDLINE was searched for English language literature on UCS with a focus on the past 20years. Given the rarity of this tumor, studies were not limited by design or number of reported patients. RESULTS UCS is biologically a de-differentiated endometrial carcinoma with its own pathogenesis and molecular profile. It commonly presents with extrauterine disease which can be identified by comprehensive surgical staging. Most UCS patients are candidates for adjuvant chemotherapy. The role of radiation is less clear. Combination therapy, while commonly used, has not been studied in depth. The high recurrence rate and poor overall survival for UCS suggest an ongoing need for clinical trials for UCS specifically. CONCLUSIONS UCS represents a distinct subtype of uterine malignancy, and should be studied as such via focused clinical trials.

A multi-institutional cohort study of adjuvant therapy in stage I–II uterine carcinosarcoma

OBJECTIVE To evaluate the impact of adjuvant post-operative therapy in women with early stage uterine carcinosarcoma. METHODS After IRB approval was obtained at all sites, a multi-center retrospective study of women with FIGO stage I-II uterine carcinosarcoma diagnosed from 1997 to 2007 was conducted. Post-operative treatment included observation (OBS), radiation (RT), chemotherapy (CT) alone or with RT (CT+RT). Data analyzed included demographic and pathologic factors, adjuvant therapy outcomes, and time-to-event information. The Kaplan-Meier method was used to estimate time-to-event functions. Cox regression modeling was used to examine the impact of selected covariates on progression free survival (PFS), and overall survival (OS). RESULTS 111 women were identified: 94 (85%) had stage I and 17 (15%) had stage II uterine carcinosarcoma. Forty-four women (40%) did not receive adjuvant therapy (OBS), 29 (26%) women had adjuvant CT, 23 (20%) women underwent RT and 15 (14%) women underwent RT+CT. Seventy-three patients were alive without disease and 38 had progressed or died at the close of data collection. In multivariate analysis, CT (p=0.003), LVSI (p<0.0001) and a pre-existing cancer (p=0.004) were most predictive of PFS. LVSI was predictive of shortened OS (p=0.01). CONCLUSIONS In women with FIGO stage I-II uterine carcinosarcoma, adjuvant chemotherapy is associated with improved PFS compared to radiation or observation alone. Ongoing clinical trials will clarify the role of chemotherapy in women with this disease.

AMG 479, a Novel IGF-1-R Antibody, Inhibits Endometrial Cancer Cell Proliferation Through Disruption of the PI3K/Akt and MAPK Pathways:

Our goal was to evaluate the therapeutic potential of a novel antibody to the insulin growth factor-1 receptor (IGF-1-R; AMG 479) in endometrial cancer cells. The endometrial cancer cell lines, ECC-1/PRAB72 and RL-95-2, were used. Treatment with AMG 479 (0.02-200 nmol/L) resulted in inhibition of cell proliferation at 72 to 120 hours. Insulin growth factor-1 (0.15-7.5 nmol/L) stimulated growth in both cell lines (range of 15%-42%, P = .0025-.0445), which could be blocked by pretreatment with AMG 479 (mean of 29% for ECC-1/PRAB72, P = .006-.007; mean of 36% for RL-95-2, P = .0002-.0045). AMG 479 suppressed IGF-1-R kinase activity in a dose-dependent manner. Cells treated with AMG 479 underwent either G1 (ECC-1/PRAB72) or G2 (RL-95-2) arrest. AMG 479 decreased human telomerase reverse transcriptase (hTERT) mRNA expression in both endometrial cancer cell lines. Treatment with AMG 479 rapidly blocked IGF-1-induced phosphorylation of IFG-1-R, Akt, and p44/42. Thus, manipulation of the IGF-1-R pathway may serve as a promising therapeutic strategy for the treatment of endometrial cancer.

Determinants of Quality Care and Mortality for Patients With Locally Advanced Cervical Cancer in Virginia

AbstractOutcomes for patients with locally advanced cervical cancer are influenced by receipt of all indicated components of quality care: early diagnosis and receipt of external beam radiation therapy, chemotherapy, and brachytherapy. We performed an observational cohort study to evaluate receipt of quality cancer care and mortality after cancer diagnosis among patients with locally advanced cervical cancer in Virginia.We queried the Virginia state cancer registry to identify patients with International Federation of Gynecology and Obstetrics Stage IB-IVA cervical cancer who were diagnosed during 2002 to 2012. We evaluated the influence of tumor-related, demographic, and geospatial factors on the receipt of indicated therapies and mortality. Treatment quality score of 0 to 3 was defined based upon the extent of receipt of the components of indicated therapy.A total of 1048 patients were identified; 33.1% received all 3 components of treatment and only 54.0% received brachytherapy. Predictors of higher quality score included younger age group versus 66+ years at diagnosis (18–42 odds ratio [OR] = 12.3, 95% confidence interval: 6.6, 23.0; 42–53 OR = 5.6, CI: 3.3, 9.5; 53–66 OR = 5.5, CI: 3.3, 9.1), lower tumor stages versus IVA (IB2 OR = 3.3, CI: 1.8, 6.2; II OR = 2.7, CI: 1.6, 4.5; IIIx OR = 2.1, CI: 1.3, 3.6), and treatment at a high-volume facility (OR 2.2, CI: 1.2, 4.2). Predictors of increased mortality included earlier year of diagnosis, higher tumor stage, treatment at a lower volume facility, and lower treatment quality score.In a cohort of locally advanced cervical cancer patients in Virginia, we identified a low rate of receipt of complete quality care for cervical cancer and a strong effect of facility volume on quality treatment and survival. Further research is needed to develop strategies to improve access to quality treatment and outcomes for cervical cancer.

The use of recombinant erythropoietin for the treatment of chemotherapy-induced anemia in patients with ovarian cancer does not affect progression-free or overall survival

Studies have suggested that erythropoietin‐stimulating agents (ESAs) may affect progression‐free survival (PFS) and overall survival (OS) in a variety of cancer types. Because this finding had not been explored previously in ovarian or primary peritoneal carcinoma, the authors of this report analyzed their ovarian cancer population to determine whether ESA treatment for chemotherapy‐induced anemia affected PFS or OS.

Robotic resection of adnexal masses during pregnancy.

OBJECTIVE To characterize the safety and feasibility of robotic adnexal surgery during pregnancy, and to compare surgical and obstetric outcomes for robotic versus laparoscopic treatment of adnexal masses during pregnancy. STUDY DESIGN A retrospective cohort study of all cases of robotic resection of adnexal masses in gravid patients performed at our institution between 2006 and 2009 compared with 50 consecutive historic laparoscopic controls performed between 1999 and 2007. RESULTS During the study period, 19 parturients underwent planned robotic resection of adnexal masses, all of which were uncomplicated. Compared with 50 consecutive laparoscopic controls, no differences in operative time, conversion to laparotomy, intraoperative or postoperative complications, or observed obstetric outcomes were apparent. The robotic cohort had a significantly shorter length of hospital stay (p < 0.01) and estimated blood loss (p = 0.02). CONCLUSION Robotic resection of adnexal masses during pregnancy appears both safe and feasible, with similar surgical outcomes when compared with a historic laparoscopic cohort.

Cervical Cancer in Women Aged 35 Years and Younger

PURPOSE Age has been evaluated as a prognostic factor in cervical cancer in both hospital- and population-based studies. Results regarding the relation of age and cervical cancer prognosis are conflicting. This study pursued a contemporary assessment of the association of extreme young age at the time of a cervical cancer diagnosis on survival. METHODS Institutional review board approval was obtained, and retrospective data collection at 2 academic institutions was performed. Inclusion criteria involved women ≤ 35 years diagnosed with cervical cancer between 1990 and 2012. Data included demographic and prognostic information pertinent to survival and progression. Characteristics of very young (≤ 25 years) and young (>25-35 years) women were compared. Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards modeling were used to assess the association of age, tumor histology, grade, stage, and parametrial involvement with progression-free survival (PFS) and overall survival (OS). FINDINGS Incident cases (n = 126) of cervical cancer in patients ≤ 35 years of age were identified of which complete clinical information was available for 114 women. Fifteen percent (17 of 114) were ≤ 25 years, with the remaining 85% (97 of 114) being 26 to 35 years of age. Race, smoking status, and marital status were comparable between the 2 groups. Squamous histology dominated overall (77 of 114; 68%) with adenocarcinoma contributing ~25% (30 of 114; 26%) of cases. The majority (96 of 114, 84%) had either stage 1A (31 of 114, 27%) or 1B (65 of 114, 57%) disease. A log-rank test revealed no evidence to infer a difference in either PFS or OS among the age groups (P = 0.511 and P = 0.340). In a univariate analysis, grade and stage significantly affected OS (P < 0.0001, P = 0.045), and stage significantly affected PFS (P < 0.0001). In multivariate modeling, presence of parametrial involvement and histologic cancer type significantly affected both PFS (P = 0.002, P = 0.001) and OS (P = 0.001, P = 0.001). IMPLICATIONS Tumor histology, parametrial involvement, and stage continue to be strong prognosticators for PFS and OS. Progression and survival outcomes are age independent in women with cervical cancer ≤ 35 years of age. Further study of a larger young cohort may potentially yield different outcomes.