Two staged phase II clinical trial of Eribulin monotherapy in advanced or recurrent cervical cancer.

BACKGROUND: Eribulin a microtubule targeting agent and analog of Halichondrin B, a natural product isolated from marine sponge H. okadai, has proven clinical efficacy in metastatic pretreated breast cancer and liposarcoma. We conducted a 2-stage Phase II study of eribulin in patients with advanced/recurrent cervical cancer to examine its clinical activity and evaluate biomarkers for predictors of response. METHODS: Women with advanced/recurrent cervical cancer after ≤1 prior chemotherapy regimen, measurable disease and ECOG performance status ≤2 were treated with eribulin (1.4 mg/m2 IV day 1 and 8, every 21 days) with tumor assessments every 2 cycles. Primary endpoint was 6-month progression-free survival (PFS6); secondary were best overall response (RECISTv1.1), toxicity (CTCAEv4.03) and overall survival (OS). Exploratory endpoints were associations of biomarkers with clinical activity. Immunohistochemistry was performed on archival tumor samples. Overexpression was defined when both intensity and distribution scores were ≥ 2. RESULTS: 32 patients enrolled from 11/2012-5/2017. 29/32 patients had prior chemotherapy with cisplatin/paclitaxel/bevacizumab (n = 12) or cisplatin/gemcitabine (n = 12) as the most common regimens. 14 patients received prior paclitaxel. 1 (3%) had a complete response, 5 (16%) had a partial response and 13 (41%) had stable disease for ORR of 19% (95% CI 8, 37). Those who are paclitaxel naïve experienced the greatest benefit with a 29% ORR (95% CI 12, 54). Patients who received prior paclitaxel responded less favorably than those who did not (p = .002) and had a shorter PFS and OS. Grade 3/4 adverse events occurring in >10% of patients were anemia (n = 12, 38%), neutropenia (n = 7, 22%) and leukopenia (n = 6, 19%). Analysis of correlative predictors of response revealed that patients who did not overexpress ßII and BAX were significantly more likely to respond to e`ribulin. PFS was significantly shorter in patients with ßII and BAX overexpression, OS was significantly shorter in those with ßIII and BAX overexpression. These associations remained after multivariate analysis. CONCLUSIONS: Eribulin shows modest activity in patients with recurrent/advanced cervical cancer with a favorable toxicity profile. Prior paclitaxel exposure is associated with decreased eribulin response. ßII, ßIII tubulin subtypes and BAX are predictors of response and survival. Eribulin may be an option for women with paclitaxel-naïve recurrent/advanced cervical cancer.

Intrauterine Manipulator Use During Minimally Invasive Hysterectomy and Risk of Lymphovascular Space Invasion in Endometrial Cancer.

OBJECTIVE: This study aimed to examine an association between intrauterine manipulator (IUM) use and frequency of lymphovascular space invasion (LVSI) in women with endometrial cancer undergoing minimally invasive hysterectomy. METHODS: A retrospective case-control study was conducted among stage I-IV endometrial cancer patients who underwent hysterectomy between 2008 and 2015. Medical records were reviewed for patient demographics, surgical details, and tumor characteristics. Women who underwent total laparoscopic hysterectomy (TLH) with IUM use were compared with women who underwent total abdominal hysterectomy (TAH). Review of archived medical record for data collection and propensity score matching were performed to adjust for background differences between TLH-IUM and TAH groups. A systematic literature review with pooled analysis was performed to examine frequency of LVSI. RESULTS: There were 687 women who underwent hysterectomy for endometrial cancer. Of those, 419 women underwent TLH with IUM use and 194 women underwent TAH. The most common type of IUM was VCare (89.5%). There was no statistically significant difference in the frequency of LVSI between the 2 groups: 15.1% for TLH-IUM vs 19.9% for TAH (P = 0.14). After propensity score matching, frequencies of LVSI were similar between the 2 groups: 21.2% for TLH-IUM vs 19.6% for TAH (P = 0.78). Systematic literature review identified 1371 cases of TLH-IUM and 1246 cases of TAH performed for endometrial cancer, and frequencies of LVSI were similar between the 2 groups (15.0% vs 13.6%, P = 0.31). CONCLUSION: Our study suggests that IUM use during TLH for endometrial cancer is not associated with increased frequency of LVSI.

Prognosis of women with apparent stage I endometrial cancer who had supracervical hysterectomy.

OBJECTIVE: To examine characteristics and survival outcomes of women with apparent early-stage endometrial cancer who had a supracervical hysterectomy. METHODS: The Surveillance, Epidemiology, and End Results Program was used to identify women with presumed stage I endometrial cancer who underwent supracervical hysterectomy between 1983 and 2012. Propensity score matching was performed to adjust background difference between supracervical hysterectomy (n=1,339) and total hysterectomy (n=110,523) cases. Endometrial cancer-specific survival (CSS) was examined by multivariable analysis expressed with adjusted-hazard ratio [HR] and 95% confidence interval [CI]. RESULTS: Supracervical hysterectomy was independently associated with younger age, low-grade disease, and small tumor size on multivariable analysis (all, P<0.001). After propensity score matching, supracervical hysterectomy remained an independent prognostic factor for decreased CSS compared to total hysterectomy (10-year rates, 91.0% versus 94.9%, adjusted-HR 1.72, 95%CI 1.20-2.47, P=0.003). Among women who received postoperative radiotherapy, 10-year CSS rates were similar between supracervical and total hysterectomy cases (84.7% versus 80.3%, P=0.40). Contrary, in the absence of postoperative radiotherapy, women undergoing supracervical hysterectomy had a significantly lower 10-year CSS rate compared to those undergoing total hysterectomy (92.1% versus 97.2%, P<0.001). Moreover, with lack of lymphadenectomy, supracervical hysterectomy was associated with decreased CSS compared to those who had total hysterectomy (91.6% versus 94.3%, P=0.018) but had similar CSS rates with lymphadenectomy (92.7% versus 91.8%, P=0.91). CONCLUSION: Although rarely performed, supracervical hysterectomy is associated with decreased survival outcome among women with apparent stage I endometrial cancer supporting the importance of avoiding this procedure in women with or at risk of endometrial cancer.

Significance of lymph node metastasis on survival of women with uterine adenosarcoma.

OBJECTIVE: Uterine adenosarcoma (UAS) is a rare gynecologic malignancy and the significance of lymph node metastasis on survival has not been well studied. METHODS: A retrospective study was performed utilizing the Surveillance, Epidemiology, End Results Program to examine UAS (n=994), endometrial stromal sarcoma (ESS, n=2910), and uterine leiomyosarcoma (LMS, n=5506) diagnosed between 1973 and 2013. The impact of lymph node metastasis on cause-specific survival (CSS) was cross-compared by multivariable analysis. Systematic literature review was conducted to examine the impact of nodal metastasis on progression-free survival (PFS) in UAS. RESULTS: UAS had the lowest incidence of lymph node metastasis among the sarcoma subtypes examined (UAS 2.9%, LMS 3.4%, and ESS 6.6%, P<0.001). Lymph node metastasis was independently associated with decreased CSS in all three tumor types (all, P<0.01); however, magnitudes of statistical significance of lymph node metastasis for CSS were similar across the three tumor types: adjusted-hazard ratio (aHR) for UAS 2.34, ESS 2.43, and LMS 2.10. Systematic literature review identified 230 unique cases of surgically treated UAS. On multivariable analysis, lymph node metastasis (aHR 4.72) had the greatest degree of significance for PFS compared to other tumor factors including sarcomatous overgrowth (aHR 2.88), heterologous elements (aHR 2.08), and deep myometrial invasion (aHR 1.51). Large tumor, deep myometrial invasion, and sarcomatous overgrowth were associated with increased risk of lymph node metastasis (all, P<0.05). CONCLUSION: While uterine adenosarcoma had a low incidence of lymph node metastasis, the impact of lymph node metastasis on survival was comparable to ESS or LMS.

Patient compliance for postoperative radiotherapy and survival outcome of women with stage I endometrioid endometrial cancer.

BACKGROUND AND OBJECTIVES: To examine characteristics and survival outcome of women with endometrial cancer who declined postoperative radiotherapy. METHODS: A retrospective study was conducted to examine surgically-treated grade 1-2 stage IB and grade 3 stage IA-IB endometrioid endometrial cancer in the Surveillance, Epidemiology, and End Results Program between 1983 and 2013 (n = 10 613). Associations of patient declination for guideline-based postoperative radiotherapy and clinico-pathological demographics or survival outcome were examined on multivariable analysis. RESULTS: There were 323 (3.0%) women who declined adjuvant radiotherapy. Women who declined postoperative radiotherapy were more likely to be older, White, Western U.S. residents, and register in recent years (all, adjusted-P < 0.05). On multivariable analysis, patient declination for guideline-based postoperative radiotherapy remained an independent prognostic factor for decreased endometrial cancer-specific survival in unstaged grade 1-2 stage IB or staged/unstated grade 3 stage IA-IB diseases (adjusted-hazard ratio 1.84, 95% confidence interval 1.34-2.51, P = 0.001). Association of patient declination for guideline-based postoperative radiotherapy and decreased overall survival remained independent in the entire cohort on multivariable analysis (adjuvant-hazard ratio 1.71, 95% confidence interval 1.44-2.02, P < 0.001). CONCLUSIONS: Our study suggested that patient compliance to guideline-based postoperative radiotherapy is a prognostic factor for women with stage I endometrioid endometrial cancer.

Endometrial cancer arising in adenomyosis versus endometrial cancer coexisting with adenomyosis: are these two different entities?

PURPOSE: While adenomyosis is one of the most common benign histologic findings in hysterectomy specimens of endometrial cancer, demographics of endometrial cancer arising in adenomyosis (EC-AIA) has not been well elucidated. The aim of this study is to evaluate histopathological findings and disease-free survival (DFS) of EC-AIA in comparison to endometrial cancer coexisting with adenomyosis (EC-A). METHODS: EC-AIA cases were identified via a systematic literature search (n = 46). EC-A cases were identified from a historical cohort that underwent hysterectomy-based surgical staging in two institutions (n = 350). Statistical comparisons of the two groups were based on univariate and multivariate analyses. RESULTS: The EC-AIA group was significantly older than the EC-A group (58.9 versus 53.8, p = 0.002). As to tumor characteristics, 63.6% of EC-AIA cases reported tumor within the myometrium without endometrial extension. The EC-AIA group was significantly associated with more non-endometrioid histology (23.9 versus 14.8%; p = 0.002) and deep myometrial tumor invasion (51.6 versus 19.4%; p < 0.001) than EC-A. Tumor grade, stage, and nodal metastasis risk were similar (all, p > 0.05). In a univariate analysis, the EC-AIA group had a significantly decreased DFS compared to EC-A (5-year rates, 72.2 versus 85.5%, p = 0.001). After controlling for age, histology, tumor grade, and stage, EC-AIA remained an independent prognostic factor associated with decreased DFS compared to EC-A (adjusted-hazard ratio 2.87, 95% confidence interval 1.44-5.70, p = 0.031). CONCLUSION: Our study demonstrated that EC-AIA has distinct tumor characteristics and a poorer survival outcome compared to EC-A. This suggests a benefit of recognition of this unique entity as an aggressive variant of endometrial cancer.

Tumor Characteristics and Survival Outcome of Endometrial Cancer Arising in Adenomyosis: An Exploratory Analysis.

BACKGROUND: Endometrial cancer arising in adenomyosis (EC-AIA) is a rare entity of endometrial cancer, and its clinical significance has not been well studied. This study aimed to examine the tumor characteristics and survival outcomes of EC-AIA. METHODS: An exploratory analysis was performed to compare EC-AIA and historical control cases. For this study, EC-AIA cases were identified via a systematic literature search using PubMed/MEDLINE with entry keywords "endometrial cancer OR uterine cancer" AND "adenomyosis" (n = 46). The control group comprised consecutive non-EC-AIA cases from four institutions that had hysterectomy-based surgical staging (n = 1294). Patient demographics, pathology results, and survival outcomes were evaluated between the two groups. RESULTS: The EC-AIA group was significantly older than the control group (58.9 vs. 55.3 years; P = 0.032). In terms of tumor characteristics, 56.5% of the EC-AIA cases showed tumor within the myometrium without endometrial extension, and the EC-AIA group was significantly more likely to have tumors with more than 50% myometrial invasion (51.6 vs. 26.6%; P = 0.002) and serous/clear cell histology (22.2 vs. 8.2%, P = 0.002) while less likely to express estrogen receptor (14.3 vs. 84.6%; P < 0.001). Grade and stage distributions were similar (P > 0.05). In the univariate analysis, the EC-AIA group had a significantly poorer disease-free survival than the control group (5-year rate: 71.4 vs. 80.6%; P = 0.014). In the multivariate analysis, with control for age, ethnicity, histology, grade, and stage, EA-CIC remained an independent prognostic factor for decreased disease-free survival (adjusted hazard ratio, 3.07; 95% confidence interval 1.55-6.08; P = 0.001). CONCLUSIONS: The study suggested that endometrial cancer arising in adenomyosis may be an aggressive variant of endometrial cancer.

Timing of Intrauterine Manipulator Insertion During Minimally Invasive Surgical Staging and Results of Pelvic Cytology in Endometrial Cancer.

STUDY OBJECTIVE: Considering the hypothetical concern of retrograde tumor spread to the peritoneal cavity by insertion of an intrauterine manipulator, we examined the correlation between the timing of manipulator insertion and the results of pelvic cytology during total laparoscopic hysterectomy (TLH) in endometrial cancer. DESIGN: Case-control study (Canadian Task Force classification II-2). SETTING: University-based hospitals. PATIENTS: Stage I to IV endometrial cancer patients who underwent TLH in which an intrauterine manipulator was used. Medical records were reviewed for patient demographics, surgical details, and tumor characteristics. INTERVENTIONS: Archived medical record review. MEASUREMENTS AND MAIN RESULTS: A total of 333 patients was identified. Cases were divided into those with intrauterine manipulator insertion after pelvic cytology sampling (Group 1, n = 103) and those with intrauterine manipulator insertion before pelvic cytology sampling (Group 2, n = 230). Types of intrauterine manipulator were similar across the 2 groups (p = .77). There was no statistical difference in the results of pelvic cytology between the 2 groups: Group 1 versus 2, atypical cells 2.9% versus 4.8% and malignant cells 5.8% versus 9.6% (p = .36). Uterine perforation related to intrauterine manipulator insertion was seen in 1.0% and .4% of each group (p = .52). In a multivariate analysis controlling for demographics and tumor characteristics, advanced-stage disease remained an independent risk factor associated with increased risk of atypical and malignant cells (adjusted odds ratio, 10.3; 95% confidence interval, 4.44-23.8; p < .001). CONCLUSION: Our study suggested that the timing of intrauterine manipulator insertion during TLH for endometrial cancer is not associated with the results of pelvic cytology.

Impact of depth and extent of lymphovascular space invasion on lymph node metastasis and recurrence patterns in endometrial cancer.

BACKGROUND AND OBJECTIVES: To determine the significance of depth and extent of lymphovascular space invasion (LVSI) on lymph node metastasis and recurrence in endometrial cancer. METHODS: A case-control study was conducted to examine LVSI-positive (n = 70) and LVSI-negative (n = 641) stage I-III endometrial cancer cases that underwent hysterectomy-based surgical staging. The risk of lymph node metastasis and distant recurrence was estimated based on LVSI patterns. RESULTS: In multivariate analysis, deep (>50% invasion), and extensive (≥7 foci/slide) LVSI patterns had a significantly increased risk of lymph node metastasis (incidence 57.6% and 72.7%, odds ratio 33.8 and 49.9, respectively, P < 0.001) as compared to other traditional uterine factors (>50% myometrial tumor invasion, cervical stromal invasion, and adnexal involvement: incidence range 30.4-37.9%, odds ratio range 3.80-7.03). Deep and extensive of LVSI patterns were both significantly correlated to distant recurrence (P < 0.001). Among women who received postoperative chemotherapy, deep and extensive LVSI patterns did not have increased risks for distant recurrence compared to no LVSI (P = 0.47 and 0.32, respectively). Among women who received postoperative radiotherapy, the depth of LVSI was significantly associated with recurrence outside the radiated field (P = 0.02). CONCLUSIONS: Depth and extent of LVSI are important predictors for lymph node metastasis and distant recurrence in endometrial cancer.

Relative Morbidity and Mortality of Panniculectomy-Combined Surgical Staging in Endometrial Cancer.

OBJECTIVE: To examine intraoperative and postoperative complication rates for surgical staging combined with panniculectomy for endometrial cancer. METHODS: A prospectively collected institutional surgical database was used to identify patients with endometrial cancer who underwent hysterectomy-based surgical staging between December 2008 and August 2014 (n = 551). The cases were grouped into surgical staging with panniculectomy (panniculectomy group, n = 11 [2.0%]), laparotomy without panniculectomy (laparotomy group, n = 208 [37.7%]), and laparoscopy (minimally invasive surgery group, n = 332 [60.3%]). Major complication and surgical wound complication rates within 30 days from surgery were compared. RESULTS: The panniculectomy group had a significantly higher body mass index compared with other approaches (panniculectomy group, laparotomy group, and minimally invasive surgery group: 60.4, 35.7, and 34.1; P < 0.001) and had a high stage I disease rate (90.9%, 61.5%, and 88.3%; P < 0.001). Mean pannus weight was 5733 g (4.4% of body weight). Intraoperative major complication rates were statistically nonsignificant across the groups (0%, 7.2%, and 4.2%; P = 0.23); however, the panniculectomy group had a significantly higher postoperative major complication rate compared with other approaches (36.4%, 16.3%, and 5.1%; P < 0.001). In multivariate analysis controlling for age, ethnicity, body habitus, medical comorbidities, and tumor factors, panniculectomy remained an independent predictor for increased risk of postoperative major complications (adjusted odds ratio, 4.37; P = 0.043). Surgical mortality rates were similar across the groups (0%, 0.5%, and 0%; P = 0.44). Among superobese patients (n = 50), intraoperative and postoperative complication rates were statistically similar across the 3 groups (all, P > 0.05). CONCLUSION: Although panniculectomy-combined surgical staging is associated with an increased risk of postoperative complications, the majority recovered uneventfully, making this approach a feasible treatment option, especially for superobese patients with endometrial cancer.

Association of Low-Dose Aspirin and Survival of Women With Endometrial Cancer.

OBJECTIVE: To examine the survival outcomes in women with endometrial cancer who were taking low-dose aspirin (81-100 mg/d). METHODS: A multicenter retrospective study was conducted examining patients with stage I-IV endometrial cancer who underwent hysterectomy-based surgical staging between January 2000 and December 2013 (N=1,687). Patient demographics, medical comorbidities, medication types, tumor characteristics, and treatment patterns were correlated to survival outcomes. A Cox proportional hazard regression model was used to estimate adjusted hazard ratio for disease-free and disease-specific overall survival. RESULTS: One hundred fifty-eight patients (9.4%, 95% confidence interval [CI] 8.8-11.9) were taking low-dose aspirin. Median follow-up time for the study cohort was 31.5 months. One hundred twenty-seven patients (7.5%) died of endometrial cancer. Low-dose aspirin use was significantly correlated with concurrent obesity, hypertension, diabetes mellitus, and hypercholesterolemia (all P<.001). Low-dose aspirin users were more likely to take other antihypertensive, antiglycemic, and anticholesterol agents (all P<.05). Low-dose aspirin use was not associated with histologic subtype, tumor grade, nodal metastasis, or cancer stage (all P>.05). On multivariable analysis, low-dose aspirin use remained an independent prognostic factor associated with an improved 5-year disease-free survival rate (90.6% compared with 80.9%, adjusted hazard ratio 0.46, 95% CI 0.25-0.86, P=.014) and disease-specific overall survival rate (96.4% compared with 87.3%, adjusted hazard ratio 0.23, 95% CI 0.08-0.64, P=.005). The increased survival effect noted with low-dose aspirin use was greatest in patients whose age was younger than 60 years (5-year disease-free survival rates, 93.9% compared with 84.0%, P=.013), body mass index was 30 or greater (92.2% compared with 81.4%, P=.027), who had type I cancer (96.5% compared with 88.6%, P=.029), and who received postoperative whole pelvic radiotherapy (88.2% compared with 61.5%, P=.014). These four factors remained significant for disease-specific overall survival (all P<.05). CONCLUSION: Our results suggest that low-dose aspirin use is associated with improved survival outcomes in women with endometrial cancer, especially in those who are young, obese, with low-grade disease, and who receive postoperative radiotherapy.