The complex triad of obesity,diabetes and race in Type I and II endometrial cancers: Prevalence and prognostic significance

Background

We examined the distribution of obesity, diabetes, and race in Type I and Type II endometrial cancers (EC) and their associations with clinical outcomes.

Methods

A multi-institutional retrospective analysis of Type I and II EC cases from January 2005 to December 2010 was conducted. Type I (endometrioid), Type II (serous and clear cell), low grade (LG) (grade 1 and 2 endometrioid), and high grade (HG) (grade 3 endometrioid, serous, clear cell) cohorts were compared. Univariate and multivariate analyses were used to determine time-to-recurrence (TTR), recurrence-free survival (RFS), and overall survival (OS).

Results

Type I EC patients were more frequently obese than Type II (66% versus 51%, p < 0.0001) and had similar rates of diabetes (25% versus 23%, p = 0.69). African-Americans (AA) had higher median BMI than Caucasians in both Type I (p < 0.001) and II (p < 0.001) ECs, and were twice as likely to have diabetes (p < 0.001). In Type I EC, DM was associated with worse RFS and OS in unadjusted and adjusted models (RFS HR 1.38, 95%CI 1.01–1.89; OS HR 1.86, 95%CI 1.30–2.67), but not with TTR. BMI was associated with improved TTR in the adjusted analysis for Type I EC (HR 0.98, 95%CI 0.95–1.0), but not with RFS or OS. There was no association between DM or BMI and outcomes in Type II or HG EC. AA race was not associated with RFS or OS on adjusted analyses in any group.

Conclusions

Obesity and diabetes are highly prevalent in Type I and II ECs, especially in AA. DM was associated with worse RFS and OS in Type I EC. Neither DM nor BMI was associated with outcomes in Type II or HG EC.     

Impact of Age-Adjusted Charlson Comorbidity score on outcomes for patients with early-stage endometrial cancer

Objectives

To determine the impact of Age-Adjusted Charlson Comorbidity (AAC) index score on survival outcomes for patients with early stage endometrial cancer.

Methods

After IRB-approval, AAC score at time of hysterectomy was retrospectively tabulated by physician chart review for 671 patients with 2009 FIGO stage I–II endometrioid adenocarcinoma. Patients were grouped based on their AAC scores as follows: 0–1 (n = 204), 2–3 (n = 293) and > 3 (n = 174). Kaplan–Meier and log-rank test methods and univariate and multivariate modeling with Cox regression analysis was used to determine significant predictors of each survival endpoint.

Results

After a median follow-up of 85 months, 225 deaths were recorded (34 from EC and 191 from other causes) with a 7-year Overall (OS) and Disease-specific survival (DSS) of 77.6% and 94.0%, respectively. Based on AAC grouping, the 7-year OS, DSS, and Recurrence-free survival (RFS) were: 92.9%, 96.8%, and 94.9% for AAC 0–1; 81.7%, 95.3%, and 89.8% for AAC 2–3: and 56%, 88.2%, and 84.9% for AAC > 3 (p < 0.0001, p = 0.005 and p = 0.013, respectively). On multivariate analyses, higher AAC score, tumor grade, lower uterine segment involvement, and lymphovascular space invasion were significantly independent predictors for shorter OS, while for DSS and RFS, higher tumor grade and lymphovascular space invasion were significant predictors of worse outcome, but higher AAC score was not.

Conclusions

Comorbidity score is as important as pathological features for predicting overall survival outcomes in patients with early-stage endometrioid endometrial carcinoma. Higher AAC scores accurately predicted for worse OS. Comorbidity score should be considered in prospective clinical trials of endometrial carcinoma.     

Metformin use and endometrial cancer survival

Objective

Impaired glucose tolerance and diabetes are risk factors for the development of uterine cancer. Although greater progression free survival among diabetic patients with ovarian and breast cancers using metformin has been reported, no studies have assessed the association of metformin use with survival in women with endometrial cancer (EC).

Methods

We conducted a single-institution retrospective cohort study of all patients treated for uterine cancer from January 1999 through December 2009. Demographic, medical, social, and survival data were abstracted from medical records and the national death registry. Overall survival (OS) was estimated using Kaplan–Meier methods. Cox models were utilized for multivariate analysis. All statistical tests were two-sided.

Results

Of 985 patients, 114 (12%) had diabetes and were treated with metformin, 136 (14%) were diabetic but did not use metformin, and 735 (74%) had not been diagnosed with diabetes. Greater OS was observed in diabetics with non-endometrioid EC who used metformin than in diabetic cases not using metformin and non-endometrioid EC cases without diabetes (log rank test (p = 0.02)). This association remained significant (hazard ratio = 0.54, 95% CI: 0.30–0.97, p < 0.04) after adjusting for age, clinical stage, grade, chemotherapy treatment, radiation treatment and the presence of hyperlipidemia in multivariate analysis. No association between metformin use and OS in diabetics with endometrioid histology was observed.

Conclusion

Diabetic EC patients with non-endometrioid tumors who used metformin had lower risk of death than women with EC who did not use metformin. These data suggest that metformin might be useful as adjuvant therapy for non-endometrioid EC.     

Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer

Background

Metformin has been associated with reduced cancer risk. The mechanisms underlying this cancer protective effect remain unknown.

Methods

“Window of opportunity” study of metformin in women with operable endometrial cancer (EC). Eleven newly diagnosed, untreated, non-diabetic patients with EC received metformin 500 mg tid from diagnostic biopsy to surgery. Fasting plasma insulin, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 1 (IGFBP-1) and insulin-like growth factor binding protein 7 (IGFBP-7) measurements were taken before and after metformin treatment. Ki-67, pAMPK, and pS6 immunohistochemistry staining was performed on the endometrial cancer before and after metformin treatment and was compared to a control group of 10 women with EC who did not receive metformin.

Results

Metformin was administered for a mean of 36.6 days. None of the patients suffered side effects requiring withdrawal from the study. The study group comprised 8 patients with endometrioid EC, and 3 non-endometrioid EC, with a mean follow-up time of 57 months. Mean plasma insulin (p = 0.0005), IGF-1 (p = 0.001), and IGFBP-7 (p = 0.0098) were significantly reduced after metformin treatment. A clear reduction in ki-67 and pS6 expression was observed by both conventional light microscope analysis and digital image analysis with a significant mean reduction in percentage of cells staining for ki-67 (9.7%, P = 0.02) and pS6 (31%, P = 0.03). In the non-treated control group expression was similar between the biopsy and the surgical specimens.

Conclusions

This pilot trial presents biological evidence consistent with anti-proliferative effects of metformin in women with EC in the clinical setting.     

Diabetes mellitus and ovarian cancer: More complex than just increasing risk

Objective

Diabetes mellitus (DM) is a risk factor for endometrial cancer and is associated with poorer outcomes in breast and colon cancers. This association is less clear in epithelial ovarian cancer (EOC). We sought to examine the effect of DM on progression-free (PFS) and overall survival (OS) in women with EOC.

Methods

A retrospective cohort study of EOC patients diagnosed between 2004 and 2009 at a single institution was performed. Demographic, pathologic and DM diagnosis data were abstracted. Pearson chi-square test and t test were used to compare variables. The Kaplan–Meier method and the log rank test were used to compare PFS and OS between non-diabetic (ND) and DM patients.

Results

62 (17%) of 367 patients had a diagnosis of DM. No differences in age, histology, debulking status, or administration of intraperitoneal chemotherapy between ND and DM patients were present, although there were more stage I and IV patients in the ND group (p = 0.04). BMI was significantly different between the two groups (ND vs. DM, 27.5 vs. 30.7 kg/m², p < 0.001). While there were no differences in survival based on BMI, diabetic patients had a poorer PFS (10.3 vs. 16.3 months, p = 0.024) and OS (26.1 vs. 42.2 months, p = 0.005) compared to ND patients. Metformin use among diabetic patients did not appear to affect PFS or OS.

Conclusions

EOC patients with DM have poorer survival than patients without diabetes; this association is independent of obesity. Metformin use did not affect outcomes. The pathophysiology of this observation requires more inquiry.     

The prognostic significance of preoperative leukocytosis in epithelial ovarian carcinoma: A retrospective cohort study

Objective

Preoperative leukocytosis is known to be a negative prognostic factor for several gynecologic malignancies, but its relationship with epithelial ovarian carcinoma (EOC) is unknown. We sought to evaluate the prognostic implications of preoperative leukocytosis for women with EOC.

Methods

We retrospectively reviewed the medical records of patients who underwent primary debulking surgery and adjuvant platinum-based chemotherapy for EOC between January 1993 and October 2011. Associations between leukocytosis and recurrence-free survival (RFS) and overall survival (OS) were determined by univariate analyses. Multivariate Cox proportional hazards regression was used to identify independent prognostic factors for RFS and OS.

Results

Of 155 women, 23 (14.8%) had leukocytosis and 132 (85.2%) did not have leukocytosis. RFS and OS were significantly shorter for women with leukocytosis than for women without leukocytosis (P = 0.009 and P < 0.0001, respectively). The mortality rate was also higher among women with leukocytosis (P < 0.0001). Multivariate analysis revealed that preoperative leukocytosis (hazard ratio [HR]: 2.15; 95% confidence interval [CI]: 1.55–4.41; P = 0.009), advanced stage (HR: 3.12; 95% CI: 1.44–6.75; P = 0.004), and optimal cytoreduction (HR: 0.38; 95% CI: 0.14-0.70; P = 0.031) were independent prognostic factors for RFS. Additionally, preoperative leukocytosis was independently associated with decreased OS (HR: 7.66; 95% CI: 2.78–21.16; P < 0.0001).

Conclusions

Among women with EOC, preoperative leukocytosis might be an independent prognostic factor for RFS and OS. A larger-scaled, prospective study is needed to verify these results.     

Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway

Objectives

To examine the effects of combination therapy with metformin and paclitaxel in endometrial cancer cell lines.

Methods

ECC-1 and Ishikawa endometrial cancer cell lines were used. Cell proliferation was assessed after exposure to paclitaxel and metformin. Cell cycle progression was assessed by flow cytometry. hTERT expression was determined by real-time RT-PCR. Western immunoblotting was performed to determine the effect of metformin/paclitaxel on the mTOR pathway.

Results

Paclitaxel inhibited proliferation in a dose-dependent manner in both cell lines with IC₅₀ values of 1-5 nM and 5-10 nM for Ishikawa and ECC-1 cells, respectively. Simultaneous exposure of cells to various doses of paclitaxel in combination with metformin (0.5 mM) resulted in a significant synergistic anti-proliferative effect in both cell lines (Combination Index < 1). Metformin induced G1 arrest in both cell lines. Paclitaxel alone or in combination with metformin resulted in predominantly G2 arrest. Metformin decreased hTERT mRNA expression while paclitaxel alone had no effect on telomerase activity. Metformin stimulated AMPK phosphorylation and decreased phosphorylation of the S6 protein. In contrast, paclitaxel inhibited AMPK phosphorylation in the ECC-1 cell line and induced phosphorylation of S6 in both cell lines. Treatment with metformin and paclitaxel resulted in decreased phosphorylation of S6 in both cell lines but only had an additive effect on AMPK phosphorylation in the ECC-1 cell line.

Conclusions

Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. This combination may be a promising targeted therapy for endometrial cancer.     

Ovary and uterus-sparing procedures for low-grade endometrial stromal sarcoma: A retrospective study of 153 cases

Objective

To discuss the optimal treatment options for low grade endometrial stromal sarcoma (LG-ESS).

Methods

Medical records of consecutive patients with LG-ESS in our institute were collected. The pertinent data, including clinicopathological characteristics, treatment and prognostic information were evaluated.

Results

A total of 153 cases of LG-ESS were included. The 5-year relapse free survival (RFS), overall survival (OS) and survival after relapse (SAR) rates were 66.1%, 95.8% and 82.9%, respectively. Ovary-sparing procedures, positive resection-margins, and myomectomy were the independent adverse factors for relapse (P < 0.0001, = 0.0041, and = 0.0075, respectively). Post-menopause, cervical involvement, and positive lymphovascular space involvement were significantly associated with survival (P < 0.0001, = 0.0020, and = 0.0163, respectively). Distance recurrence and macroscopically residual tumors negatively affected SAR (P = 0.0137 and = 0.0004, respectively). No benefit was found for lymphadenectomy in terms of both RFS and OS (P = 0.1187 and = 0.5138, respectively). Initial ovary-sparing procedures and myomectomy had no impact on OS (P = 0.0810 and = 0.8845, respectively). Adjuvant treatment had a slightly beneficial effect both on OS and SAR.

Conclusion

Hysterectomy with bilateral salpingo-oophorectomy and complete resection of the macroscopic lesion should be treated as the initial and salvage mainstay treatments for LG-ESS patients. Ovary-sparing procedures could be considered for young women without cervical involvement; however, long-term follow-up should be mandatory. Myomectomy should only be conserved for young patients with a strong desire for future fertility, with fully informed consent; hysterectomy was recommended after the completion of pregnancy and delivery. However, the roles of lymphadenectomy and adjuvant treatment deserve further investigation.     

A prospective feasibility study of radiation and concurrent bevacizumab for recurrent endometrial cancer

Objectives

To determine the toxicity and survival rates in a trial of concurrent bevacizumab and external beam radiation (EB) for patients with recurrent endometrial or ovarian cancer.

Methods

Nineteen women with recurrent endometrial (n = 15) or ovarian (n = 4) cancer with gross disease involving the vaginal cuff, and/or pelvic nodes and/or para-aortic nodes, cancer were enrolled between 2008 and 2010. All patients received bevacizumab during radiation. Toxicity was assessed at baseline, weekly during treatment and every 3 months for at least 1 year after treatment.

Results

All patients completed EB on schedule. For the 15 patients with recurrent endometrial cancer, the 1- and 3-year progression-free survival (PFS was) 80%/67% and overall survival (OS) was 93%/80%. Patients that had a vaginal cuff recurrence alone had a 1- and 3-year PFS of 75%/63% and OS of 100%/75%. Two patients with pelvic node involvement did not recur throughout the entire follow-up period. The 5 patients with para-aortic node involvement had a 1- and 3-year PFS of 80%/60% and OS of 80%/80%. Of the 4 ovarian cancer patients 3 relapsed with 1- and 3-year PFS of 80%/40% and OS of 100%/60%. Toxicities included thrombosis and 1 embolic event in the setting of metastastic disease. No gastrointestinal perforations were noted.

Conclusions

Delivering bevacizumab with concurrent radiation provides excellent local tumor control and survival for women with recurrent endometrioid endometrial cancer, particularly those with unresectable nodes. Caution must be used in those at highest risk of developing metastatic disease given the increased risk of thromboembolic events. This regimen may be considered for recurrent gynecologic malignancies in future trials.     

Overall survival after pelvic exenteration for gynecologic malignancy

Background

Five-Year survival after pelvic exenteration for gynecologic malignancies has been reported as high as 60%. The objective of this study was to determine overall survival (OS) after pelvic exenteration and evaluate factors impacting outcome.

Methods

A retrospective review of all women who underwent pelvic exenteration at our institution between February 1993 and December 2010 was performed. OS was defined as time from exenteration to date of death or last contact. Survival analysis was performed using the Kaplan Meyer method. Multivariate analysis was performed to determine the impact of clinical and pathologic factors on survival outcomes.

Results

One hundred sixty patients with gynecologic malignancy underwent pelvic exenteration. Five-year recurrence free survival (RFS) was 33% (95%CI 0.25–0.40). Factors which negatively impacted RFS included shorter treatment-free interval (p = .050), vulvar primary (p = .032), positive margins (p < .001), lymphovascular space invasion (LVSI, p < .001), positive lymph nodes (p < .001) and perineural invasion (p = 0.030). In multivariate analysis, positive margins (p = .040), positive nodes (p < .001) and lymphovascular space invasion (LVSI, p = .003) retained a significant impact on RFS.Five-year OS was 40% (95% CI 0.32–0.48). Factors which negatively impacted OS included vulvar primary (p = .04), positive margins (p < .001), LVSI (p < .001), positive lymph nodes (p < .001) and perineural invasion (p = .008). In multivariate analysis, positive nodes (p = .001) and LVSI (p = .001) retained a significant impact on OS.

Conclusion

Five-year OS after pelvic exenteration was 40%. Survival outcomes have not significantly improved despite improvements in technique and patient selection. Multiple non-modifiable factors at the time of exenteration are associated with poor survival.     

Is time to recurrence after hysterectomy predictive of survival in patients with early stage endometrial carcinoma?

Purpose/objective(s)

To determine the prognostic significance of time to recurrence (TTR) on overall survival (OS) and disease-specific survival (DSS) following recurrence in patients with stage I-II uterine endometrioid carcinoma.

Materials/methods

After IRB approval, we retrospectively identified 57 patients with recurrent endometrioid carcinoma who were initially treated for FIGO 1988 stages I-II between 1987 and 2009. The Kaplan-Meier approach and Cox regression analysis were used to estimate OS and DSS following recurrence and identify factors impacting outcomes.

Results

Median follow-up times were 54.8 months from hysterectomy and 19.8 months after recurrence. Median time to recurrence was 20.2 months. Twenty-eight (47%) patients had a recurrence < 18 months after hysterectomy and 29 (53%) had a recurrence ≥ 18 months. Both groups were evenly matched regarding initial pathological features and adjuvant treatments. The median OS and DSS in patients with TTR < 18 months was shorter than those with TTR ≥ 18 months, but not statistically significant (p = 0.216). TTR did not impact outcomes after loco-regional recurrence, but for extrapelvic recurrence, a shorter TTR resulted in worse OS and DSS (p = 0.03). On multivariate analysis, isolated loco-regional recurrence (HR 0.28, p = 0.001) and salvage radiation therapy (HR 0.47, p = 0.045) were statistically significant independent predictors of longer OS following recurrence. TTR as a continuous variable or dichotomized was not predictive of OS or DSS.

Conclusions

In our study, the prognostic impact of time to recurrence was less important than the site of recurrence. While not prognostic for the entire cohort or for patients with loco-regional recurrence, TTR < 18 months was associated with shorter OS and DSS after extrapelvic recurrence.     

Prognostic factors and outcomes in endometrial stromal sarcoma with the 2009 FIGO staging system: A multicenter review of 114 cases

Objective

To assess prognostic factors associated with disease-related survival in endometrial stromal sarcoma (ESS) using the 2009 FIGO staging system.

Methods

From January 1990 to January 2012, 114 patients with ESS were identified at the Samsung and Asan Medical Center and data were retrospectively analyzed.

Results

Ten (8.7%) patients died of the disease and 33 (28.9%) patients relapsed. The 5- and 10-year overall survival (OS) rates for the entire cohort were 92.6% and 87.1%, respectively, and the 5- and 10-year recurrence-free survival (RFS) rates were 71.8% and 52.1%, respectively. The estimated median survival after recurrence for the 33 patients whose tumors relapsed was 133 months (95% CI, 7.7–258.4), and 5-year survival after recurrence was 68.9%. Stage I (P = 0.006), estrogen and/or progesterone receptor (ER/PR) positivity (P = 0.0027), and no nodal metastasis (P = 0.033) were associated with a good prognosis for OS in the univariate analysis. Ovarian preservation was revealed to be an independent predictor for poorer RFS (HR, 6.5; 95% CI, 1.23–34.19; P = 0.027). Positivity for ER/PR (HR, 0.05; 95% CI, 0.006–0.4; P = 0.006) and cytoreductive resection of recurrent lesions (HR, 0.14; 95% CI, 0.02–0.93; P = 0.042) were independent predictors of better survival after recurrence.

Conclusions

Stage, expression of ER/PR, and nodal metastasis are significantly associated with OS in ESS. Bilateral salpingo-oophorectomy (BSO) as the primary treatment and cytoreductive resection of recurrent lesions should be considered for improving survival of patients with ESS.     

Comparison of clinical outcomes of patients with clear cell and endometrioid ovarian cancer associated with endometriosis to papillary serous carcinoma of the ovary

Objective

The aim of this investigation was to compare outcomes of patients with clear cell carcinoma (CCC) and endometrioid carcinoma (EC) of the ovary associated with endometriosis to patients with ovarian papillary serous carcinoma (PSC).

Methods

Patients with CCC and EC of the ovary associated with endometriosis were identified and matched by age and stage to PSC controls. Student's t test and chi square test were used to analyze continuous and categorical data. The Kaplan–Meier method was used for survival analysis.

Results

67 cases associated with endometriosis were identified, of which 45 were arising in endometriosis. Cases were matched to 134 PSC controls. 27 patients with tumors associated with endometriosis presented at stage I (40.3%), 27 at stage II (40.3%), ten at stage III (14.9%) and three at stage IV (4.5%). There was no difference in rate of optimal cytoreduction or response to chemotherapy in cases vs. PSC controls. There was a significant increase in synchronous endometrial cancer in tumors associated with endometriosis compared to PSC (25.4% vs. 3.7%; P < 0.001). 18 cases (26.9%) had recurrent disease vs. 55 (41%) controls (P = 0.03). The 5-year disease-free survival (DFS) and overall survival (OS) of patients with tumors associated with endometriosis compared to PSC controls were 75% vs. 55% (P = 0.03) and 85% vs. 77% (P = 0.2), respectively.

Conclusions

Patients with tumors associated with endometriosis had a higher rate of synchronous endometrial cancer. Cases also demonstrated a lower rate of recurrence and improved 5 year DFS; however, this did not translate into a difference in OS.     

Outcomes of patients with low-risk endometrial cancer surgically staged without lymphadenectomy based on intra-operative evaluation

Objective

The objective of the study was to evaluate clinical outcomes in patients with stage I endometrial cancer undergoing surgical management without lymphadenectomy based on intra-operative assessment for low-risk disease.

Methods

Between 2000 and 2009, a total of 179 patients were surgically staged without lymphadenectomy for low-risk stage I endometrial cancer. Low-risk cancer was defined by intra-operative criteria based on both gross and frozen tissue microscopic evaluation: 1) G1 or G2 endometrioid histology; 2) myoinvasion < 50%; 3) no cervical disease, and 4) no intra-abdominal metastasis. Records were reviewed for postoperative complications, pathological diagnoses, adjuvant radiation treatment, cancer recurrence, and mortality.

Results

Morbidity, cancer recurrence, and disease-specific mortality were low. Postoperative complications occurred in 5 patients (2.8%). Nine patients (5.0%) were offered adjuvant radiation for higher risk disease diagnosed on final pathology. Radiation morbidity was minimal: grade 1 vaginal toxicity in 2 patients. Three patients (1.7%) experienced recurrent cancer with mean time to recurrence of 43.7 months. Five year overall survival was 95.8%. The five year probability of disease-specific death was 1.1%.

Conclusion

In an institution with reliable capability of pathological frozen tissue diagnosis, omission of lymph node dissection is a reasonable option in the surgical management of those patients with low-risk disease diagnosed by intra-operative factors.     

Clinical outcomes following 3D image-guided brachytherapy for vaginal recurrence of endometrial cancer

Purpose

To evaluate clinical outcomes for women with recurrent endometrial cancer treated with 3D image-guided brachytherapy

Methods and materials

44 women, of whom 13 had received prior RT, received salvage RT for vaginal recurrence from 9/03 to 8/11. HDR or LDR interstitial brachytherapy was performed under MR or CT guidance in 35 patients (80%); 9 (20%) had CT-guided HDR cylinder brachytherapy. The median cumulative dose in EQD2 was 75.5 Gy. Actuarial estimates of local failure (LF), disease-free (DFS) and overall survival (OS) were calculated by Kaplan–Meier.

Results

Histologic subtypes were endometrioid (EAC, 33), papillary serous/clear cell (UPSC/CC, 5) and carcinosarcoma (CS, 6). The 2-year DFS/OS rates were 75%/89% for EAC and 11%/24% for UPSC/CC/CS (both p < 0.01). On MVA, high tumor grade was associated with recurrence (HR 3.2 for grade 2, 9.6 for grade 3, p < 0.01). The LF rate at 2 years was 4% for patients without versus 39% for those with prior RT (p = 0.1). Patients who had prior RT received lower cumulative doses at recurrence (66.5 Gy vs. 74.4 Gy, p < 0.01). The 2-year DFS/OS rates with and without prior RT were 26%/55% and 72%/80% (both p = 0.1). Four patients (9%) experienced grade 3 late toxicity, including 3 of 13 (23%) in the re-irradiation setting and 1 of 31 (3%) with no prior radiotherapy.

Discussion

3D image-guided brachytherapy results in excellent local control for women with recurrent endometrial cancer, particularly with cumulative EQD2 doses greater than 70 Gy. Successful salvage of vaginal recurrence is related to tumor grade and histologic subtype.     

Retrospective analysis of prognostic variables and clinical outcomes in surgically staged intermediate risk endometrial carcinoma

Objective

To identify independent prognostic variables for surgically staged intermediate risk endometrial carcinoma as defined by the Gynecologic Oncology Group 99 (GOG99) criteria.

Study design

Retrospective study of 239 patients with FIGO stage IB-occult IIB endometrioid type endometrial cancer, who were primarily treated with comprehensive staging surgery. Data were collected on clinicopathological variables, extent of primary surgery, postoperative adjuvant treatment, and patterns of recurrences. Kaplan–Meier survival curves were used to estimate disease free survival (DFS) and overall survival (OS), and multivariate Cox regression models were used to identify independent prognostic variables. The median follow-up time was 67 months (range, 12–183 months).

Results

The 5-year DFS and OS were 91.0% and 93.0%, respectively. On univariate Kaplan–Meier analysis, age > 60 years, deep myometrial invasion (MI), presence of lymph vascular invasion (LVSI), and negative progesterone receptor (PR) status were significantly associated with diminished 5-year DFS and OS. The univariate analysis on patterns of failures demonstrated that patients with older age or positive LVSI were more inclined to develop locoregional recurrence, while PR status and the depth of MI had a statistically significant impact on distant failure. On multivariate analysis, PR status, age, and the depth of MI were independent prognostic variables for 5-year DFS, and age was the only independent prognostic variable for 5-year OS. LVSI and age were independent prognostic variables for locoregional recurrence, while PR status and depth of MI were independent prognostic variables for distant recurrence.

Conclusions

Age, depth of MI, PR status and presence of LVSI are of independent prognostic value for intermediate risk endometrial cancer. The presence of these variables warrants consideration when deciding upon treatment strategies.     

Peritoneal cytology: A risk factor of recurrence for non-endometrioid endometrial cancer

Objective

We compared the impact of positive peritoneal cytology on prognosis between patients with endometrioid and non-endometrioid endometrial carcinoma.

Methods

We retrospectively reviewed the medical records of 490 patients diagnosed with endometrial cancer between 2000 and 2012. These patients were divided into two groups: endometrioid and non-endometrioid histologies. We compared the patients' baseline characteristics, tumor recurrence patterns, and survival to determine the prognostic factors and how they differed between the two groups.

Results

Of the included patients, 448 had endometrioid histology and 42 had non-endometrioid histology. A total of 27 patients experienced tumor recurrence: 17 with endometrioid histology (4.0%) and 10 with non-endometrioid histology (23.8%). Compared to endometrioid type, non-endometrioid type exhibited higher rates of recurrence (p < 0.01). Recurrence sites of the non-endometrioid group were mainly peritoneal seeding (p < 0.01) and distant organ metastasis (p = 0.02). Risk factors for tumor recurrence included patient age, stage of disease, and adjuvant treatment for endometrioid type. On the other hand, in cases of non-endometrioid endometrial cancer, positive peritoneal cytology was an independent prognostic factor regardless of tumor stage (HR, 15.34; 95% CI, 3.55–66.25; p < 0.01). Among cases with non-endometrioid histology, median recurrence-free survival significantly differed between the negative peritoneal cytology group and the positive peritoneal cytology group (120 months versus 22 months, respectively; p < 0.01).

Conclusions

Positive peritoneal cytology is an independent prognostic factor for patients with non-endometrioid endometrial cancer.     

Determination of metformin transfer across the human placenta using a dually perfused ex vivo placental cotyledon model

Objective

The aim of the study was to quantify and characterize metformin transfer across the human placenta using an ex vivo placental perfusion model.

Study design

Placentas were obtained from vaginal deliveries or caesarean sections and selected cotyledons were cannulated and dually perfused. Metformin (1 μg/ml) and a permeability reference marker, antipyrine (50 μg/ml), were added to the maternal circulation. Each perfusion experiment was conducted for 180 min while samples were taken from the maternal and fetal compartments. The integrity and viability of the placenta were determined by measuring the flow rates, fetal artery inflow pressure, and hCG production during the experiments.

Results

Six complete experimental set-ups were completed. The maternal–fetal transport rates for metformin and antipyrine were 10.61 ± 2.85% and 30.98 ± 5.62%, respectively. The clearance index, calculated as the ratio between the permeabilities of metformin and antipyrine, was 0.34 ± 0.05.

Conclusion

The results indicate that metformin is able to cross the mature human placenta; thus, fetal exposure must be considered when treating pregnant women with metformin.     

Adjuvant radiation in early stage,unfavorable histology endometrial carcinoma is associated with improved local control and survival

Objective

Unfavorable histology endometrial carcinomas confer worse prognosis. We determined the association of adjuvant radiation on local recurrence and survival for unfavorable, early stage endometrial cancer.

Methods

We retrospectively identified 125 patients who had a hysterectomy for early stage (FIGO IA), unfavorable histology (clear cell, papillary serous or grade 3 endometrioid), endometrial carcinoma treated between 1992 and 2011. Patients were restaged according to current FIGO 2009 guidelines. Primary endpoint was local control and secondary endpoints were distant recurrence and overall survival.

Results

The median age of the cohort was 67 years old with a mean follow up 152 months. Adjuvant radiation was delivered in 60 patients (48%). There were a total of 24 recurrences; 5 had local–regional recurrences, 4 local and distant recurrence, 12 distant only recurrences, and 3 had unspecified recurrences. The 5-year local–regional control was 97.8% in patients who received radiation and 80.1% in patients who did not receive radiation (p = 0.018). The 5-year overall survival rate was 68.1% if patients did not receive radiation and 84.9% if they did receive radiation (p = 0.0062). On univariate analysis, only radiation (HR 0.12, 95% CI: 0.03 to 0.49, p-value = 0.018) was associated with a significant increase in local relapse free survival.

Conclusions

Adjuvant radiation therapy was significantly associated with an improvement in local–regional control and overall survival in patients with unfavorable histology, early stage endometrial cancer.     

Effects of metformin on mammalian target of rapamycin in a mouse model of endometrial hyperplasia

Objective

The effects of metformin on S6K1, which is a crucial effector of mTOR signaling, and on endometrium were studied in a mouse model of endometrial hyperplasia induced by unopposed estradiol or tamoxifen.

Study design

Forty-eight oophorectomized Balb/c mice were randomly assigned to receive saline, tamoxifen citrate (4 mg/kg), 17-beta estradiol hemihydrate (4 mg/kg), metformin (50 mg/kg), tamoxifen citrate (4 mg/kg) with metformin (50 mg/kg), or estradiol (4 mg/kg) with metformin (50 mg/kg) for 3 days. Histological markers of uterotrophy, including luminal epithelial cell height and density of endometrial glands were quantified for each slide. Immunohistochemical expression of PCNA and S6K1 was evaluated. H-score was used for S6K1 expression. Statistical analysis was performed using Student's t-test for comparison of two continous variables and one-way ANOVA for comparison of multiple variables.

Results

Mice treated either with tamoxifen or estradiol had significantly increased density of endometrial glands and epithelial heights compared to vehicle-only or metformin-only group (p < 0.001). Addition of metformin to tamoxifen or estradiol treated mice significantly decreased the density of endometrial glands and epithelial cell heights (p < 0.05). Addition of metformin to tamoxifen significantly decreased the H-score of S6K1 (p < 0.05) and the immunohistochemical expression of PCNA (p < 0.05) in uterine lining epithelium, glandular and stromal cells. Addition of metformin to estradiol significantly decreased the H-score of S6K1 (p < 0.05) and the immunohistochemical expression of PCNA (p < 0.05) in uterine lining epithelium, glandular and stromal cells.

Conclusion

Metformin seems to have possible antiproliferative effects on the endometrium of estradiol or tamoxifen treated mice via inhibiting the mTOR mediated S6K1 activation.