Validation of an Endometrial Tumor Diameter Model for Risk Assessment in the Absence of Lymph Node Mapping.

PURPOSE: This study aimed to assess the optimal tumor diameter for predicting lymphatic metastasis and to determine intraoperatively the need for lymph node dissection in patients with endometrioid endometrial cancer. METHODS: Military beneficiaries diagnosed with stage I-III endometrioid endometrial cancer during 2003-2016 who had at least 7 pelvic and/or paraaortic lymph nodes removed during the time of hysterectomy were studied. Tumor diameter was compared against the presence of positive nodes, using the prior models of 20 mm (ie, Mayo model) and 50 mm (ie, Milwaukee model), to determine the false-negative rate of each threshold. A separate analysis was completed to determine the optimal diameter for our population. Receiver operating characteristic curve analysis models of tumor diameter were evaluated for model fit and predictive power of lymph node involvement. RESULTS: Of the 1224 patients with endometrioid endometrial cancer included, 13% (n=160) had positive lymph node involvement. Tumor sizes ranged from 1 mm to 100 mm. In contrast to Mayo and Milwaukee models (ie, Mayo, Milwaukee), the optimal tumor diameter independent of myometrial invasion and grade of tumor to predict lymph node metastasis was found to be 35 mm. CONCLUSIONS: Endometrioid endometrial cancer tumor diameter of 35 mm was found to be the optimal threshold for lymphadenectomy when the operating surgeon has no knowledge of tumor invasion.

Can Magnetic Resonance Imaging Predict Pathologic Findings for Endometrioid Endometrial Cancer?

This pilot study aimed to assess the feasibility of precisely measuring tumor diameter and myometrial invasion in patients with endometrioid endometrial cancer (EEC) using preoperative contrast-enhanced magnetic resonance imaging (MRI). Adult patients with confirmed diagnosis of complex hyperplasia with atypia or EEC were included. Three radiologists separately measured tumor diameter and myometrial invasion. Basic descriptive statistics were used to describe patient characteristics and to compare radiology- and pathology-measured tumor diameter and myometrial invasion. Using the pathology results for tumor diameter as the gold standard for comparison, at least 1 radiologist was able to predict largest tumor diameter within 5 mm for 41.7% of patients. Similarly, based on pathology results for myometrial invasion, at least 1 radiologist was able to predict myometrial invasion within 5% for 50% of patients. All radiologists were able to predict superficial (<50%) or deep (≥50%) myometrial invasion for 75% of patients, with greater sensitivity, specificity, and accuracy for deep myometrial invasion. Given variation among radiologic measurements, it is difficult to recommend preoperative MRI as a basis for measuring tumor diameter and myometrial invasion. Even so, the ability to predict superficial versus deep myometrial invasion may benefit patients with EEC for whom surgery is not a viable option or for those seeking fertility-sparing treatment options.

Tumor diameter as a predictor of lymphatic dissemination in endometrioid endometrial cancer.

OBJECTIVES: To assess the utility of tumor diameter (TD) for predicting lymphatic dissemination (LD) and determining need for lymphadenectomy following diagnosis of endometrioid endometrial cancer. METHODS: Patients diagnosed with stage I-III endometrioid endometrial cancer during 2003-2013 who underwent pelvic or para-aortic lymphadenectomy during hysterectomy were studied. Intraoperative predictors of LD included TD, grade, myometrial invasion (MI), age, body mass index, and race/ethnicity. Candidate logistic regression models of LD were evaluated for model fit and predictive power. RESULTS: Of 737 cancer patients, 68 (9.2%) were node-positive. Single-variable models with only continuous TD (c-statistic 0.77, 95% CI 0.71-0.83) and dichotomous TD with 50-mm cut-off (TD50; c-statistic 0.73, 95% CI 0.67-0.78) were significantly more predictive than with the standard 20-mm cut-off (c-statistic 0.56, 95% CI 0.53-0.59). Overall, the most important LD predictors were TD50 and MI3rds (three-category form). The best candidate model (c-statistic 0.84, 95% CI 0.80-0.88) suggested odds of LD were five times greater for TD >50mm than ≤50mm (OR 4.91, 95% CI 2.73-8.82) and six and ten times greater for MI >33% to ≤66% (OR, 5.70; 95% CI, 2.25-14.5) and >66% (OR 10.2, 95% CI 4.11-25.4), respectively, than ≤33%. Best-model false-negative (0%) and positive (57.2%) rates demonstrated marked improvement over traditional risk-stratification false-negative (1.5%) and positive (76.2%) rates (c-statistic 0.77, 95% CI 0.72-0.82). CONCLUSIONS: Tumor diameter is an important predictor of LD. Our risk model, containing modified forms of MI and TD, yielded a lower false-negative rate and can significantly decrease the number of lymphadenectomies performed on low-risk women.

Robotic surgical management of endometrial cancer in octogenarians and nonagenarians: analysis of perioperative outcomes and review of the literature.

The primary aim of this article is to report the outcomes of octogenarians and nonagenarians who have undergone robotic surgery for endometrial cancer. A multi-institutional research consortium was created to evaluate the utility of robotics for gynecologic surgery (benign and malignant). IRB approval was obtained at each institution. A multi-institutional HIPPA compliant database was then created and analyzed for all patients that underwent robotic-assisted surgery with staging for endometrial cancer between the April 2003 and January 2009. In total, 395 patients were identified. A subset of patients between the ages of 80 and 95 years were then identified and analyzed for demographic data and perioperative outcomes. Twenty-seven patients in this age group were identified who underwent robotic-assisted hysterectomy and staging. The median age was 84, and median body mass index was 28. Comorbidities such as diabetes mellitus and hypertension were identified in 22 and 74% of patients, respectively. Over one-half (56%) of the patients reported a prior abdominal surgery. Final pathological analysis demonstrated that 88% of all patients had either Stage I or II disease. The median operative time was 192 min. The median estimated blood loss was 50 cc, and the median lymph node count was 16. The median hospital stay was 1.0 day. The overall intraoperative and postoperative complication rate was 7.4 and 33%, respectively. No patient received a blood transfusion. There was one conversion to laparotomy (3.7%). A comparison of the outcomes of the elderly cohort to those of all patients in the database (control group) revealed that there was no statistically significant difference between the groups in terms of operative time, blood loss, hospital stay, nodal yield, or conversion rate. Intraoperative complications were statistically similar between the groups; however, postoperative complications were significantly higher in the elderly cohort. We conclude that robotic surgery is safe, feasible, and expands surgical options for octogenarians and nonagenarians diagnosed with endometrial cancer. Age should not be considered a contraindication for robotic surgical management of patients with endometrial cancer.

A multiinstitutional experience with robotic-assisted hysterectomy with staging for endometrial cancer.

OBJECTIVE: To report perioperative outcomes and learning curve characteristics from a multiinstitutional experience with robotic-assisted surgical staging for endometrial cancer. METHODS: A multiinstitutional robotic surgical consortium was created to evaluate the usefulness of robotics for gynecologic oncology surgery. An analysis of a multiinstitutional database of all patients who underwent robotic surgery for endometrial carcinoma between April 2003 and January 2009 was performed. Records were reviewed for demographic data and perioperative outcomes. Individual surgeon outcomes were analyzed as well in an attempt to evaluate characteristics of learning with incorporation of robotic technology. RESULTS: Four hundred five patients were identified who underwent robotic surgery for endometrial cancer. Mean age was 62.2 years and mean body mass index was 32.4. Fifty-five percent of patients reported a prior abdominal surgery. Final pathologic analysis demonstrated that 89.6% of all patients had stage I and II disease. Mean operative time was 170.5 minutes. Mean estimated blood loss was 87.5 mL. Mean lymph node count was 15.5. Mean hospital stay was 1.8 days. Intraoperative complications occurred in 3.5% of the patients and conversion to laparotomy occurred in 6.7%. Postoperative complications were reported in 14.6% of the patients. For the group, fewer than 10 cases were required to achieve proficiency with the procedure. CONCLUSION: Robotic technology may level the playing field between the novice and expert laparoscopist for endometrial cancer staging. Prospective trials should be undertaken to compare robotic and laparoscopic approaches to treat endometrial cancer. LEVEL OF EVIDENCE: III.

A multi-institutional experience with robotic-assisted radical hysterectomy for early stage cervical cancer.

OBJECTIVE: The purpose of the study is to report a multi-institutional experience with robotic-assisted radical hysterectomy to treat patients with early stage cervical cancer with respect to perioperative outcomes. METHODS: A multi-institutional robotic surgical consortium consisting of five board-certified gynecologist oncologist in distinct geographical regions of the United States was created to evaluate the utility of robotics for gynecologic surgery (benign and malignant). Between April 2003 and August 2008, a total of 835 patients underwent robotic surgery for benign gynecologic disorders and/or gynecologic malignancies by a surgeon in the consortium. IRB approval was obtained and data was collected in a prospective fashion at each institution. For the purposes of the study, a multi-institutional HIPPA compliant database was then created for all patients that underwent robotic-assisted surgery between the April 2003 and August 2008. This database was queried for all patients who underwent a robotic-assisted type II or III radical hysterectomy for Stage IA1 (+vsi)-IB2 cervical carcinoma. Forty-two patients were identified. Records were then reviewed for demographic data, medical conditions, prior abdominal or pelvic surgeries, and follow-up. The perioperative outcomes analyzed included: operative time (skin-skin), estimated blood loss (EBL), length of hospital stay, total lymph node count, conversion to laparotomy, and operative complications. RESULTS: From a database of 835 patients who underwent robotic surgery by a gynecologic oncologist, a total of 42 patients who underwent a robotic-assisted type II (n=10) or type III (n=32) radical hysterectomy for early stage cervical cancer were identified. Demographic data demonstrated a median age of 41 and a median BMI of 25.1. With regard to stage, seven patients (17%) were Stage IA2, twenty-eight patients (67%) were Stage IB1 and six patients (14%) were Stage IB2. There was a single patient with Stage IA1 cervical cancer with vascular space invasion who underwent a type II radical hysterectomy. The overall median operative time was 215 min. The overall median estimated blood loss was 50 cc. No patient received a blood transfusion. The median lymph node count was 25. The median hospital stay was 1 day. Positive lymph nodes were detected in 12% of the patients. Pelvic radiotherapy or chemo-radiation was given to 14% of the patients based on final surgical pathology. Intraoperative complications occurred in 4.8% of the patients and included one conversion to laparotomy (2.4%) and one ureteral injury (2.4%). Postoperative complications were reported in 12% of the patients and included a DVT (2.4%), infection (7.2%), and bladder/urinary tract complication (2.4%) The conversion rate to laparotomy was 2.4%. CONCLUSIONS: Robotic-assisted radical hysterectomy is associated with minimal blood loss, a shortened hospital stay, and few operative complications. Operative time and lymph node yields are acceptable. This data suggests that robotic-assisted radical hysterectomy may offer an alternative to traditional radical hysterectomy. This series contributes to the growing literature on robotic-assisted radical hysterectomy and prospective comparisons with traditional radical hysterectomy are needed.

Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists.

The anti-cancer activities and toxicities of retinoic acid (RA) and synthetic retinoids are mediated through nuclear RA receptors (RARs) and retinoid X receptors (RXRs) that act as transcription factors. Heteroarotinoids (Hets), which contain a heteroatom in the cyclic ring of an arotinoid structure, exhibit similar anti-cancer activities, but reduced toxicity in vivo, in comparison to parent retinoids and RA. A new class of Flexible Hets (Flex-Hets), which contain 3-atom urea or thiourea linkers, regulate growth and differentiation similar to RA, but do not activate RARs or RXRs. In addition, Flex-Hets induce potent apoptosis in ovarian cancer and in head and neck cancer cell lines through the intrinsic mitochondrial pathway. In this study, 4 cervical cancer cell lines were growth inhibited by micromolar concentrations of Flex-Hets to greater extents than RAR/RXR active retinoids. The most potent Flex-Het (SHetA2) inhibited each cell line of the National Cancer Institute's human tumor cell line panel at micromolar concentrations. Oral administration of Flex-Hets (SHetA2 and SHetA4) inhibited growth of OVCAR-3 ovarian cancer xenografts to similar extents as administration of a RAR/RXR-panagonist (SHet50) and Fenretinide (4-HPR) in vivo. None of these compounds induced evidence of skin, bone or liver toxicity, or increased levels of serum alanine aminotransferase (ALT) in the treated mice. Topical application of Flex-Hets did not induce skin irritation in vivo, whereas a RAR/RXR-panagonist (NHet17) and a RARgamma-selective agonist (SHet65) induced similar irritancy as RA. In conclusion, Flex-Hets exhibit improved therapeutic ratios for multiple cancer types over RAR and/or RXR agonists.

Sensitization of cervical cancer cell lines to low-dose radiation by retinoic acid does not require functional p53.

OBJECTIVE: Current therapy for cervical cancer includes radiation therapy. Retinoic acid (RA) can increase the sensitivity of cervical cancer cell lines to radiation. The mechanism of this sensitization may not involve the p53 protein because the human papillomavirus (HPV) E6 protein, which is present in the majority of cervical cancers, promotes p53 degradation. The objective of this study was to determine if p53 is involved in the mechanism of RA radiosensitization. METHOD: The effects of radiation on cervical (SiHa, CC-1, and C33a) and vulvar (SW962) cancer cell lines under various experimental conditions were evaluated using clonogenic, Coulter Counter, electrophoretic mobility shift (EMSA) and a multi-probe RNase protection assay of p53-inducible genes. RESULTS: RA (5 microM 9-cis-RA) radiosensitized the SiHa and CC-1 cell lines that contain HPV-degraded p53, but did not radiosensitize the SW962 cell line, which is HPV negative and contains wild-type p53, nor the C33a cell line, which contains mutant p53 (R273C). Expression of mutant p53 (R273H) in SiHa cells increased the growth rate, but did not prevent RA-induced differentiation or radiosensitization at clinically relevant doses. Inhibition of p53 transactivation with pifithirin alpha did not prevent RA radiosensitization of SiHa at 5 Gy. RA repressed c-fos mRNA expression in control and irradiated SiHa cultures, but did not repress bcl-x(L), p53, GADD45, p21, bax, bcl-2, or mcl-1 mRNA expression. CONCLUSIONS: The mechanism of RA radiosensitization does not require functional p53 and may involve c-fos in cervical cancer cell lines.

A comparison of stages IB1 and IB2 cervical cancers treated with radical hysterectomy. Is size the real difference?

OBJECTIVE: To compare stages IB1 and IB2 cervical cancers treated with radical hysterectomy (RH) and to define predictors of nodal status and recurrence. METHODS: Patients with stage IB cervical cancers undergoing RH between 1990 and 2000 were evaluated and clinicopathological variables were abstracted. The perioperative complication rate, estimated blood loss (EBL), and OR time were also tabulated. Variables were analyzed using X(2) and t tests. Disease-free survival (DFS) was calculated by Kaplan-Meier method. Multivariate analysis was performed via stepwise logistic regression. Cox-proportional hazards were used to identify independent predictors of recurrence. RESULTS: RH was performed on 109 stage IB1 and 86 stage IB2 patients. Mean age, EBL, and perioperative complication rates were similar. Overall, 38 patients (14 IB1 vs. 24 IB2) had positive nodes (P = 0.01) including 9 patients with positive para-aortic nodes (2 IB1 and 7 IB2). Parametrial involvement (PI) and outer 2/3 depth of invasion (DOI) were significantly more common in the IB2 tumors as well. Patients with IB2 disease received adjuvant radiation more frequently than IB1 patients (52% vs. 37%, P = 0.04). Univariate predictors of nodal status included lymphovascular space involvement (LVSI) (P = 0.001), DOI (P = 0.011), PI (P = 0.001), and stage (P = 0.011). Multivariate analysis identified only LVSI (OR 6.4, CI 2.4-17, P = 0. 0002) and PI (OR 8, CI 3.1-20, P = 0. 0001) as independent predictors of positive nodes. With a median follow-up of 35 months, estimates of DFS revealed tumor size (P = 0.008), nodal status (P = 0.0004), LVSI (P = 0.002), PI (P = 0.004), and DOI (P = 0.0004) as significant univariate predictors. Neoadjuvant chemotherapy, age, grade, histology, and adjuvant radiation were not associated with recurrence. The significant independent predictors of DFS were LVSI (ROR 5.7, CI 2-16, P = 0.0064) and outer 2/3 DOI (OR 5.8, CI 2-20, P = 0.0029). Neither tumor size nor nodal status was a significant predictor of DFS. CONCLUSIONS: The prognosis in stage IB cervical cancer seems to be most influenced by presence of LVSI and DOI and not by tumor size as the staging criteria would suggest. These factors are best determined pathologically after radical hysterectomy. This report contains the largest comparison of IB1 and IB2 patients managed by RH. Tumor size failed to predict recurrence or nodal status when stratified by LVSI, DOI, and PI. Treatment decisions based on tumor size alone should be reconsidered.

Surgical-pathological predictors of disease-free survival and risk groupings for IB2 cervical cancer: do the traditional models still apply?

OBJECTIVE: To evaluate how the independent predictors of recurrence for stage IB2 cervical cancers treated with up-front radical hysterectomy apply to established risk models. METHODS: Patients with IB2 cervical cancers diagnosed from 1990 to 2000 were identified from tumor registries of two institutions. Patients were classified into risk groups: high-risk (HR) (positive nodes, parametria, or margins), intermediate-risk (IR) (positive lymph vascular space involvement (LVSI) with any cervical stromal invasion (CSI), or (-) LVSI and > middle- CSI), or low-risk (LR) (absence of HR or IR characteristics). Disease-free survival (DFS) was estimated by Kaplan-Meier method and comparisons between subgroups were studied by log rank. A Cox proportional hazards model was used to determine independent predictors of recurrence. RESULTS: We identified 86 patients with stage IB2 tumors treated by RH. We found 34% of patients to be HR, 60% IR, and 6% LR. Of the 52 IR patients, 28 had (+) LVSI with superficial, middle, and outer 1/3 CSI, and 24 had (-) LVSI with middle or outer 1/3 invasion. Overall, postoperative adjuvant radiation (PRT) was used in 52% of the 86 patients, including 0/5 LR, 16/52 IR, and 29/29 HR patients. Univariate predictors of recurrence were pelvic nodal disease, (+) LVSI, (+) parametria, outer 1/3 CSI, and tumor size > 6 cm. Age, grade, histology, and the use of postoperative radiation were not associated with recurrence. Multivariate analysis identified LVSI as the only independent predictor of recurrence (RR 5.2, P = 0.03). Two-year DFS for LR, IR, and HR patients was 100%, 83%, and 60%, respectively. Only 4/24 (17%) IR patients with (-) LVSI got PRT compared with 12/28 (43%) of IR patients with (+) LVSI. The 2-year DFS for IR patients with (-) LVSI was 96%. IR (+) patients recurred more frequently with a 2-year DFS of 71%. CONCLUSIONS: Overall, 66% of patients with IB2 disease were classified as having low or intermediate-risk disease. IR patients with (-) LVSI and all LR patients did well with surgery alone. This study defines the independent importance of LVSI and questions the utility of published IR models when applied to stage IB2 cervical cancer.