Rabbie K. Hanna

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 IC(50) values of 1-5nM and 5-10nM for Ishikawa and ECC-1 cells, respectively. Simultaneous exposure of cells to various doses of paclitaxel in combination with metformin (0.5mM) 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.

Perioperative Outcomes of Robotically Assisted Hysterectomy for Benign Cases With Complex Pathology

OBJECTIVE: To report on the perioperative outcomes after robotically assisted total hysterectomy for benign indications in a large patient population with predominantly complex pathology. METHODS: One hundred fifty-two patients underwent robotic hysterectomy for noncancer indications from May 2005 to May 2008. A systematic chart review of consecutive robotic cases was conducted based on preoperative and perioperative characteristics of each patient. Each case was evaluated for its complexity based on preoperative diagnosis, prior pelvic or abdominal surgery, patient’s body mass index, and uterine weight. RESULTS: The overall operative time was 122.9 minutes, estimated blood loss was 79.0 mL, and there were three (2.1%) intraoperative complications, with no perioperative blood transfusions or conversions. There were five (3.5%) patients with postoperative complications, and length of hospital stay was 1.0 days on average. Of the characteristics indicating complexity, only uterine weight greater than 250 g resulted in significantly increased operative times, attributable to increased morcellation time. CONCLUSION: Robotically assisted total hysterectomy for benign indications in patients with complex pathology is feasible, with low morbidity and a short hospital stay. This study suggests that robotic assistance facilitates the use of a minimally invasive approach in high-risk patient populations. LEVEL OF EVIDENCE: III

Prognostic impact of lymphadenectomy in clinically early stage malignant germ cell tumour of the ovary

Background:The aim of this study was to determine the impact of lymphadenectomy and nodal metastasis on survival in clinical stage I malignant ovarian germ cell tumour (OGCT).Methods:Data were obtained from the National Cancer Institute registry from 1988 to 2006. Analyses were performed using Students t-test, Kaplan–Meier and Cox proportional hazard methods.Results:In all, 1083 patients with OGCT who have undergone surgical treatment and deemed at time of the surgery to have disease clinically confined to the ovary were included 590 (54.48%) had no lymphadenectomy (LND−1) and 493 (45.52%) had lymphadenectomy. Of the 493 patients who had lymphadenectomy, 441 (89.5%) were FIGO surgical stage I (LND+1) and 52 (10.5%) were upstaged to FIGO stage IIIC due to nodal metastasis (LND+3C). The 5-year survival was 96.9% for LND−1, 97.7% for LND+1 and 93.4% for LND+3C (P=0.5). On multivariate analysis, lymphadenectomy was not an independent predictor of survival when controlling for age, histology and race (HR: 1.26, 95% CI: 0.62–2.58, P=0.5). Moreover, the presence of lymph node metastasis had no significant effect on survival (HR: 2.7, 95% CI: 0.67–10.96, P=0.16).Conclusion:Neither lymphadenectomy nor lymph node metastasis was an independent predictor of survival in patients with OGCT confined to the ovary. This probably reflects the highly chemosensitive nature of these tumours.

Predictors of reduced relative dose intensity and its relationship to mortality in women receiving multi-agent chemotherapy for epithelial ovarian cancer

OBJECTIVE There is limited information concerning the role of relative dose intensity (RDI) on clinical outcomes in solid tumors. The objectives of our study were to evaluate the prognostic significance of RDI and predictors of reduced RDI in women with newly diagnosed advanced stage epithelial ovarian carcinoma (EOC) treated with platinum-based chemotherapy. METHODS A multi-center retrospective study of women with FIGO stage III-IV epithelial ovarian cancer treated postoperatively with multi-agent intravenous chemotherapy between 1995 and 2009 was conducted. Data were obtained to include the first four chemotherapy cycles administered. Outcomes included: (1) planned and delivered relative dose intensity (RDI), (2) progression-free (PFS) and overall (OS) survival. Survival estimates were based on Kaplan and Meier method, and multivariate analyses were based on logistic regression and Cox proportional hazards regression. RESULTS Evaluable subjects included 325 women. With median follow-up of 34 months (range, 0.4-170), progression or recurrence was recorded in 241 (73.9%) and death in 179 (54.9%). In multivariate analysis, predictors of reduced planned RDI were: treatment off research protocols (odds ratio [OR]=4.3; P<0.001) and BSA >2m(2) (OR=6.14; P<0.001); predictors of reduced delivered RDI were: BMI over 30 kg/m(2) (OR=2.35; P=0.008) and use of carboplatin (OR=2.71; P=0.008). In multivariate analysis, the following factors were independently associated with OS: delivered RDI <85% (hazard ratio [HR]=1.71; P=0.003) and elevated CA-125 at cycle 1 (HR=2.29; P=0.017). CONCLUSION In this retrospective analysis, reduced chemotherapy RDI for ovarian cancer was associated with lower OS, but not PFS, despite adjustment for established prognostic factors.

The prognostic significance of age in surgically staged patients with Type II endometrial carcinoma

OBJECTIVE Many studies have examined the impact of older age on tumor recurrence and survival after hysterectomy for patients with endometrioid carcinoma. However, there is paucity of data examining the prognostic significance of age in patients with Type II endometrial carcinoma. The study was conducted to determine the prognostic impact of age in this patient population. MATERIALS AND METHODS In this Institutional Review Board (IRB)-approved study, our prospectively-maintained database of 1305 patients with endometrial cancer was reviewed. Seventy-two consecutive patients with serous and clear carcinoma 2009 FIGO stages I-II were identified with at least one year follow-up after surgical staging. Patients with mixed histology and those who received preoperative therapy were excluded. All the patients underwent surgical staging from 1989 to 2009. Their medical records were reviewed. The study cohort was divided into two groups based on their age at hysterectomy (≤ 65 vs. >65). Patients demographics, pathologic features and treatment-related factors were compared. The impact of age on recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) were calculated. Following univariate analysis, multivariate modeling was done using step-wise Cox proportional hazards analysis to assess the impact of age on clinical outcomes after adjusting for various clinical variables. RESULTS Median follow-up for the study cohort was 45 months (range 13-246). Fifty percent of patients received adjuvant platinum-based chemotherapy and/or adjuvant radiation treatment (RT). Thirty-five patients were older than 65 years (49%) and 37 were ≤ 65 (51%). There were no significant differences between the two groups in regard to race (African American vs Caucasian), FIGO stage, number of lymph nodes dissected, lymphovascular space involvement (LVSI), or adjuvant therapy received. There were more clear cell histology in the younger age group (p=0.035). Patients >65 years old developed more recurrences with a 5-year RFS of 59% compared to 84% for younger patients (p=0.036). The five-year DSS was not statistically different between the two groups (68% vs. 79%, respectively with p=0.313). 5-year OS was significantly shorter in the elderly patients (58% vs. 78% with p=0.014). On multivariate analysis, the presence of LVSI, not receiving RT and age >65 were independent predictors of worse RFS (p=<0.001, 0.005, and 0.040 respectively). CONCLUSION In this study for surgically staged FIGO I-II patients with Type II endometrial carcinoma, age more than 65 years is a significant adverse prognostic factor for tumor recurrence.

Predictors of severe and febrile neutropenia during primary chemotherapy for ovarian cancer

OBJECTIVE To identify factors that increase the risk of neutropenic events in women with advanced ovarian carcinoma receiving initial chemotherapy. METHODS Multi-center retrospective study of women with FIGO stage III-IV epithelial ovarian cancer treated postoperatively with multi-agent intravenous chemotherapy from 1995 to 2008. Outcomes were severe (SN; absolute neutrophil count [ANC]<500/mm(3)) and febrile neutropenia (FN; ANC<1000/mm(3) and temperature>38.1°C). Cumulative risk of neutropenic events was estimated by Kaplan Meier method. Multivariate analysis was by Cox proportional hazard regression. RESULTS Three hundred twenty-six patients met inclusion criteria. There were 251 SN events among 140 (43%) patients and 24 FN events among 22 (7%) patients. Univariate predictors of SN were body surface area<2.0m(2) (p=0.03), body mass index (BMI)<30 kg/m(2) (p<0.01), Caucasian race (p<0.01), treatment on research protocols (p<0.01), non-carboplatin-containing regimens (p<0.01), and planned relative dose intensity (RDI)>85% of standard (p=0.02). Women over age 60 were more likely to develop FN (p=0.05). Multivariate predictors of SN were treatment on research protocols (hazard ratio [HR] 1.93; p<0.01), Caucasian race (HR 2.13; p=0.01), and planned RDI>85% (HR 1.69; p=0.05); predictors of FN were age>60 (HR 2.84; p=0.05) and non-carboplatin containing regimens (HR 4.06; p<0.01). CONCLUSION While SN is fairly common, FN occurs infrequently in women with EOC undergoing taxane and platin-based chemotherapy and primary prophylactic growth factor support is not indicated. However, women older than 60 years of age receiving non-carboplatin containing regimens are at higher risk for FN and warrant closer surveillance.

The Role of Surgery and Radiation Therapy in the Management of Gestational Trophoblastic Disease

The primary management of hydatidiform moles remains surgical evacuation followed by human chorionic gonadotropin level monitoring. Although suction dilatation and evacuation is the most frequent technique for molar evacuation, hysterectomy is a viable option in older patients who do not wish to preserve fertility. Despite advances in chemotherapy regimens for treating malignant gestational trophoblastic neoplasia, hysterectomy and other extirpative procedures continue to play a role in the management of patients with both low-risk and high-risk gestational trophoblastic neoplasia. Primary hysterectomy can reduce the amount of chemotherapy required to treat low-risk disease, whereas surgical resections, including hysterectomy, pulmonary resections, and other extirpative procedures, can be invaluable for treating highly selected patients with persistent, drug-resistant disease. Radiation therapy is also often incorporated into the multimodality therapy of patients with high-risk metastatic disease. This review discusses the indications for and the role of surgical interventions during the management of women with hydatidiform moles and malignant gestational trophoblastic neoplasia and reviews the use of radiation therapy in the treatment of women with malignant gestational trophoblastic neoplasia.

The prognostic impact of the ratio of positive lymph nodes on survival of epithelial ovarian cancer patients.

To study the prognostic significance of ratio of positive to examined lymph nodes (LNR) on survival of patients with node positive epithelial ovarian cancer (NPEOC).

Influence of Comorbidity on the Risk of Death: A Single Institution Study of 1132 Women With Early-stage Uterine Cancer

Purpose/Objective(s): The impact of competing medical comorbidity on survival endpoints in women with early stage endometrial carcinoma (EC) is not well studied. The study goal was to utilize a validated comorbidity scoring system to determine its impact on all-cause mortality as well as on recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) in patients with early-stage EC. Materials and Methods: For this IRB-approved study, we reviewed our prospectively maintained uterine cancer database of 1720 patients. We identified 1132 patients with EC FIGO stages I-II who underwent hysterectomy from 1984 to 2011. Age-adjusted Charlson Comorbidity Index (AACCI) at time of hysterectomy was retrospectively calculated by physician chart review. The cause of death (uterine cancer-related and unrelated) was correlated with AACCI. Univariate and multivariate modeling with Cox regression analysis was used to determine significant predictors of OS, DSS, and RFS. The Kaplan-Meier and the log-rank test methods were used to evaluate survival outcomes. Results: After a median follow-up of 51 months, 262 deaths were recorded (42 from EC [16%], and 220 [84%] from other causes). Median AACCI score for the study cohort was 3 (range, 0 to 15). On the basis of AACCI, patients were grouped as follows: 0 to 2 (group 1, n=379), 3 to 4 (group 2, n=532), and ≥5 (group 3, n=221). By AACCI grouping, the 5-year RFS, DSS, and OS were 95%, 98%, and 97% for group 1, 89%, 95%, and 87% for group 2, and 86%, 95% and 72% for group 3 (P<0.0001). The cause of death in the first 10 years after hysterectomy in our study was mainly non-uterine cancer-related (78% vs. 22% for uterine cancer-related) causes. On multivariate analyses, higher AACCI, lymphovascular space invasion (LVSI), higher tumor grade, age, and involvement of the lower uterine segment were significant predictors of shorter OS. On multivariate analysis for DSS and RFS, only high tumor grade and LVSI were significant predictors. Conclusions: The cause of death for women with early stage EC is mainly nonuterine cancer-related. Comorbidity score is a significant predictor of OS in our study cohort. Comorbidity scores may be useful as a stratification factor in any prospective clinical trial for women with early-stage EC.

Disparities in treatment and survival between African-American and white women with vaginal cancer

OBJECTIVE The study aims to compare the difference in treatment and survival between White (W) and African American (AA) patients with vaginal cancer (VC). METHODS Patients with a diagnosis of invasive vaginal cancer were identified from Surveillance, Epidemiology, and End Results (SEER) program from 1988 to 2007 and were divided into White (W) and African American (AA) subgroups. Students t test, Kaplan-Meier survival methods, and Cox regression proportional hazards were performed. RESULTS A total of 2675 patients met the inclusion criteria, with histologic distribution of squamous cell carcinoma (SCC; 2190, 82%) and adenocarcinoma (AC; 485, 18%); 2294 (85.8%) were W, and 381 (14.2%) were AA. Median age was 69 for W and 65 for AA (p<0.001). SCC and AC were equally distributed between W and AA. Advanced stage disease (FIGO III and IV) was more prominent in AA compared with W (30.4% vs. 23.1%, p=0.019). Radiation therapy was utilized equally in both racial groups; however, surgical treatment alone or combined with radiation therapy was more frequent in W compared with AA (27.7% vs. 17.5%, p<0.001). The 5-year survival was 45% in W and 38.6% in AA (p=0.008). In multivariate analysis, AA had significantly poorer survival compared with Whites when controlling for age, histology, stage, grade and treatment modality (HR 1.2, 95% CI 1.1-1.4, p=0.007). CONCLUSIONS African American women with vaginal cancer were more likely to present, at a younger age, advanced stage and less likely to receive surgical treatment. Our data suggests that AA race is an independent predictor of poor survival in vaginal cancer.