Board-certified specialty training program in radiation oncology in a war-torn country: Challenges, solutions and outcomes.

BACKGROUND: Residency programs leading to board certification are important for safe and competent Radiation Oncology (RO) practice. In some developing nations, there is a gap in this field. This work addresses the experience that was accomplished to establish such a program in Iraq despite all the challenges that faces a country under war. METHODS: Descriptive report of challenges faced in a developing country that is still reeling from war, the steps taken to overcome these challenges and outcomes after graduation of two classes. RESULTS: After over 18 months of prerequisite technical and logistical preparations, a group of local and external faculty members were invited to establish the required syllabus of a structured RO residency program in Iraq. It is comprised of a total of 100 post-graduate academic credits over a 48-months period after clinical internship. First year evaluations included regular practical assessments; seven in-house papers covering RO, cancer and radiation biology, medical physics, radiological anatomy and diagnostic oncology, tumor pathology, onco-pharmacology, and medical statistics, research methodology, and cancer epidemiology, followed by a comprehensive examination. Subsequent evaluations were on an annual bases with enrollment in the American College of Radiology In-Training examination in RO. Final assessment included logbook and skills' reviews, graduation thesis or peer-review publication, two-papers' written examination, and an exit practical examination. CONCLUSIONS: Given the political, economic and social difficulties in post-war Iraq, it was a major challenge to establish a residency program in RO. Despite the significant difficulties, the first residency program leading to board certification in RO was successfully started in Iraq. The new specialists will help in addressing the shortage of radiation oncologists in the country.

A Simplified Risk Stratification Method for Women With Stage I Endometrial Carcinoma.

OBJECTIVES: Available risk stratification methods for women with endometrial carcinoma are controversially defined. We sought to develop a simplified and an individualized prognostic index for cancer recurrence in women with International Federation of Gynecology and Obstetrics (FIGO) stage I endometrial carcinoma, solely of endometrioid histology. MATERIALS AND METHODS: We identified 976 women who underwent a hysterectomy and did not receive any adjuvant therapy. Cox proportional hazards model was used to identify independent predictors of recurrence. Prognostic groups were created based on the number of independent predictors of recurrence (0, 1, or 2 or 3 risk factors). These groups were then validated using a separate cohort of 611 women treated at another academic institution. The model's performance for predicting cancer recurrence was measured by the concordance probability estimate along with a 95% confidence interval. RESULTS: Median follow-up was 65 months. The final recurrence model included 3 risk groups based on 3 independent predictors of recurrence (tumor grade 2 or 3, the presence of lymphovascular space invasion and stage IB). Five-year recurrence rates were 4%, 16%, and 44% for groups 0, 1, and 2 or 3, respectively. The performance of the model was very good with a concordance probability estimate of 0.72 and 0.80 for the development and validation cohorts, respectively. CONCLUSIONS: On the basis of 3 well-known prognostic factors, we have developed and externally validated a simplified prognostic model that accurately predicts cancer recurrence in women with stage I endometrial carcinoma. This simplified predictive tool may be helpful in estimating individualized risk of recurrence and guide counseling with regard to adjuvant treatment.

Adjuvant External Radiation Impacts Outcome of Pelvis-limited Stage III Endometrial Carcinoma: A Multi-institutional Study.

BACKGROUND: Adjuvant therapy choice for women with FIGO stage III endometrial carcinoma (EC) is controversial. We investigate the comparative benefit of adjuvant chemotherapy (CT) alone, radiation therapy alone (RT) or in combination (chemotherapy and radiation therapy [CRT]) with respect to recurrence-free survival (RFS) and overall survival (OS) in women with pelvis-limited (PL) EC (stage IIIA, IIIB, and IIIC1). MATERIALS AND METHODS: A multi-institutional database of 270 surgically staged women with PLEC was analyzed. Univariate log-rank analyses and Cox regression multivariate analyses (MVA) were performed to identify factors associated with RFS and OS. RESULTS: Median RFS and OS were 112 and 130 months, respectively, for the full cohort. Adjuvant treatment was CT in 21%, RT in 27%, and CRT in 47%. Age, year of treatment, grade, histology, and adjuvant treatment were significantly associated with RFS and OS on univariate analysis. PLEC patients receiving CT alone fared worse in terms of RFS (P=0.07 relative to RT and <0.01 relative to CRT). On MVA, CRT retained significantly improved RFS relative to CT (hazard ratio for recurrence 0.38, P<0.01). PLEC patients receiving RT or CRT had improved OS compared with CT, P<0.01 and 0.03, respectively. On MVA, both RT only and CRT retained association with improved OS relative to CT alone (hazard ratio for death, 0.43, P=0.02 and 0.40, P<0.01, respectively). CONCLUSIONS: For surgically staged PL stage III EC, treatment regimens incorporating RT were associated with improved survival endpoints relative to CT alone. As such, RT should be considered an important component in the adjuvant management of stage III PLEC.

What Is the Optimal Adjuvant Treatment Sequence for Node-Positive Endometrial Cancer? Results of a National Cancer Database Analysis.

OBJECTIVE: The optimal sequence of administering chemotherapy (CT) and radiation treatment (RT) in women with node-positive endometrial carcinoma (EC) remains controversial. We used the National Cancer Database to evaluate overall survival (OS) in women with advanced EC receiving different sequences of adjuvant therapy. METHODS: The National Cancer Database was queried for female adults with International Federation of Gynecology and Obstetrics 2009 stage IIIC1 to IIIC2 EC diagnosed from 2004 to 2012 treated with hysterectomy and adjuvant CT and RT. Overall survival was compared between sequential treatment (CT followed by RT) and concurrent treatment (CT and RT within 4 weeks). χ tests assessed differences by sequence and various clinical variables. Log-rank test and Cox proportional hazards models evaluated OS. Risk factors related to OS were identified by univariate and multivariate analyses. RESULTS: Of 1826 patients, 67% (1218) received sequential treatment and 33% (608) received concurrent treatment. The median follow-up was 49.2 months. The sequential treatment group had a better 5-year OS (67% [95% confidence interval = 64%-70%]) than the concurrent treatment group (62% [95% confidence interval = 57%-66%]) (P = 0.004). On multivariate analysis, the strongest predictors of worse OS were increasing age (hazard ratio [HR] = 1.04 [1.02-1.06], P = 0.0003), type 2 versus type 1 EC (HR = 1.60 [1.06-2.43], P = 0.03), grade 3 versus 1 (HR = 2.64 [1.23-5.67], P = 0.01), residual disease or positive margin versus negative margin (HR = 2.25 [1.43-3.56], P = 0.0005), and concurrent versus sequential treatment (HR = 1.67 [1.15-2.40], P = 0.006). CONCLUSIONS: This study suggests that upfront CT followed by RT may be a better treatment sequence for adjuvant therapy in women with advanced EC.

Survival outcomes and patterns of failure in women with stage IIIC2 endometrial carcinoma.

OBJECTIVES: Para-aortic lymph node involvement in women with endometrial carcinoma (EC) is a poor prognostic factor. Many studies have included women with stage IIIC2 in cohorts of patients with advanced stage disease. The aim of this study was to analyze survival outcomes and patterns of failure in women with solely stage IIIC2 EC. METHODS: We identified women with FIGO stage IIIC2 EC who underwent surgical staging at our institution. In addition to descriptive analyses of patient demographics, tumor characteristics, and adjuvant treatment received, univariate log-rank analyses and Cox regression multivariate analyses (MVA) were performed to identify predictors of recurrence-free (RFS), disease-specific (DSS) and overall survival (OS). RESULTS: A total of 72 women were included in this study cohort. The median follow-up time was 43 months. The median number of positive para-aortic lymph nodes was one. Of the 61 women (84.7%) who received adjuvant therapy, 40 women (65.6%) received chemotherapy and radiation therapy (CRT), 17 women (27.9%) received chemotherapy alone (CT), and only 4 women (6.6%) received radiation therapy alone. Thirty-seven women (51.4%) experienced disease recurrence. Distant metastasis was the most common pattern of failure (73%). Five-year RFS, DSS, and OS were 48%, 51%, and 48%, respectively. Due to small study size, our exploratory multivariate analysis demonstrated that histologic grade was the only significant prognostic factor for DSS (p=0.03) and OS (p=0.02). The type of adjuvant therapy did not sustain its independent predictive significance for RFS, DSS and OS. CONCLUSIONS: Our findings suggest that almost half of women with stage IIIC2 can be cured with surgical staging and adjuvant therapies. The most common pattern of failure was distant metastasis calling for further optimization of systemic therapy.

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

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

The K-Technique: A Novel Technique for Laparoscopic Apical Suspension Using Barbed Sutures.

OBJECTIVES: Hysterectomy is among the most common gynecologic procedures performed for women, second only to cesarean sections, and the proportion of it performed laparoscopically continues to increase. Addressing apical support at the time of the hysterectomy is crucial to minimizing the risk of posthysterectomy prolapse. Barriers to addressing apical support include the lack of experience in laparoscopic suturing and knot tying that require advanced skills and dexterity. The K-technique is a novel modification of the uterosacral ligament suspension procedure using the knot-less barbed suture technology, rendering suturing easier and quicker to perform. METHOD: The vaginal cuff epithelium is closed with 2 unidirectional barbed sutures that are started at the lateral fornices and ran until the midsection. The same sutures will then serially purchase the anterior and posterior vaginal endopelvic fascia and the midsegment of the uterosacral ligament. Two more passes are thrown through the same structures, yet farther laterally, back and forth. A video illustration of the procedure is attached. RESULTS: Eighteen patients underwent the procedure with no urinary tract injuries documented by cystoscopy and no postoperative morbidity documented during the 6-week postoperative follow-up period. Limited short- and long-term follow-up data are reassuring, but more will be needed to confirm the efficacy of barbed sutures in prolapse repair. CONCLUSIONS: The K-technique combines the conventional uterosacral ligament suspension concept with the ease, effectiveness, and safety of barbed sutures. The technique might aid the surgeon to add the apical vaginal support when indicated.

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.

Survival endpoints for young women with early stage uterine endometrioid carcinoma: a matched analysis.

OBJECTIVES: Younger age is thought to be a favorable prognostic factor in women with endometrial carcinoma (EC). Survival endpoints were compared between two matched groups of patients with early stage EC: women 45 years or younger and women older than 45 years. METHODS AND MATERIALS: Two matched groups of patients were created based on stage, grade, lymph node dissection and adjuvant management. Recurrence-free (RFS), disease-specific (DSS) and overall survival (OS) were calculated. RESULTS: A total of 525 patients (88 younger patients and 437 older patients, matched 1:5) were included in this study. The two groups were well balanced except for less myometrial invasion in the younger patients. There were no significant differences between younger and older patients in regards to 5-year RFS (94% vs. 91%, p=0.6902). Similarly, there was no significant difference in regards to DSS (96% vs. 97%, p=0.9000). While 5-year OS was similar for both groups (89% vs. 89%, p=0.9942), 10-year OS was longer in the younger group (83% vs. 68% with p=0.13). On multivariate analysis for RFS, the presence of lymphovascular space invasion was the only predictor of shorter RFS (p=0.0007). Tumor grade (p=0.0002) and lower uterine segment involvement (p=0.0141) were independent predictors of shorter DSS. Older age (p<0.001) and stage II (p=0.01) were the only predictors of shorter OS. CONCLUSIONS: When matched based on tumor stage, grade and adjuvant management, our study suggests that there is no difference in survival endpoints between younger and older patients with early stage endometrial carcinoma.

Predictors of Survival After Recurrence in Women With Early-Stage Endometrial Carcinoma.

OBJECTIVE: Factors predictive of survival after recurrent early-stage endometrial carcinoma have not been thoroughly investigated. The purpose of this study was to explore factors that impact disease-specific survival (DSS) and overall survival (OS) after recurrence in women with early-stage endometrial carcinoma. MATERIALS AND METHODS: After institutional review board approval, we identified 104 women with 2009 International Federation of Gynecology and Obstetrics stage I to II uterine endometrioid carcinoma who developed disease recurrence between January 1990 and December 2014. The Kaplan-Meier approach and Cox regression analysis were used to assess DSS and OS after recurrence and to determine factors influencing these survival end points. RESULTS: Median age of the study cohort was 65 years with a median follow-up time of 42.8 months after hysterectomy. Median time to recurrence was 15.8 months. Recurrences were diagnosed in 60 patients (57.7%) who were originally managed with observation after hysterectomy and in 44 patients (42.3%) who were initially managed with adjuvant radiation treatment. Fifty-six patients (54%) had pelvic recurrence (vaginal and/or pelvic), whereas 48 (46%) had extrapelvic recurrence. Five-year DSS and OS for the entire study population was 44% and 37%, respectively. Five-year DSS and OS were longer for patients with pelvic recurrence compared with patients with extrapelvic recurrence (66% vs 18% and 55% vs 17%, P < 0.0001). Five-year DSS was also longer for radiation-naive patients than for radiation-treated patients (51% vs 34%, P = 0.023). On multivariate analysis of DSS and OS, pelvic recurrence (P < 0.001) was the only significant predictor of longer DSS and OS. CONCLUSIONS: In women with recurrent early-stage endometrioid carcinoma, our study suggests that site of recurrence (pelvic vs extra pelvic) is the only predictor of survival. In addition, we found that radiation naivete and pelvic recurrence correlated with longer DSS and OS.

Adjuvant therapy of uterine clear cell carcinoma: a review.

PURPOSE: Uterine clear-cell carcinoma (UCCC) is a rare subset of type II endometrial carcinoma with a poor prognosis relative to the most common type of endometrioid carcinoma. Due to its rarity, there has been limited direct evidence of the efficacy of specific adjuvant therapy posthysterectomy in women with UCCC. We present a review of current literature regarding adjuvant therapy of uterine clear cell carcinoma. METHODS: We searched for English-language publications through Pubmed using a combination of the following key words: endometrial carcinoma, clear cell carcinoma, recurrence, prognosis, adjuvant therapy, radiation treatment and chemotherapy. Due to the rarity of UCCC, studies were not limited by design or number of patients. RESULTS: There is a paucity of randomized prospective controlled studies focusing on UCCC adjuvant therapy. Findings have largely been derived from retrospective studies of type II endometrial carcinomas or all endometrial cancers as a group. Very few retrospective studies were found to focus on UCCC adjuvant therapy, although certain larger studies did have subset analyses of UCCC patients. CONCLUSIONS: For early stage disease, locoregional radiotherapy, especially vaginal brachytherapy, has evidence of efficacy. The therapeutic gain of radiotherapy may be further improved with the addition of systemic chemotherapy. Evidence for combined radiation therapy with systemic chemotherapy in women with advanced stage UCCC has remained debatable. UCCC-specific studies are needed to determine the best adjuvant therapy for UCCC without the confounding effects of USC and other endometrial cancers.

Interval between hysterectomy and start of radiation treatment is predictive of recurrence in patients with endometrial carcinoma.

PURPOSE: Adjuvant radiation therapy (RT) has been shown to improve local control in patients with endometrial carcinoma. We analyzed the impact of the time interval between hysterectomy and RT initiation in patients with endometrial carcinoma. METHODS AND MATERIALS: In this institutional review board-approved study, we identified 308 patients with endometrial carcinoma who received adjuvant RT after hysterectomy. All patients had undergone hysterectomy, oophorectomy, and pelvic and para-aortic lymph node evaluation from 1988 to 2010. Patients' demographics, pathologic features, and treatments were compared. The time interval between hysterectomy and the start of RT was calculated. The effects of time interval on recurrence-free (RFS), disease-specific (DSS), and overall survival (OS) were calculated. Following univariate analysis, multivariate modeling was performed. RESULTS: The median age and follow-up for the study cohort was 65 years and 72 months, respectively. Eighty-five percent of the patients had endometrioid carcinoma. RT was delivered with high-dose-rate brachytherapy alone (29%), pelvic RT alone (20%), or both (51%). Median time interval to start RT was 42 days (range, 21-130 days). A total of 269 patients (74%) started their RT <9 weeks after undergoing hysterectomy (group 1) and 26% started ≥ 9 weeks after surgery (group 2). There were a total of 43 recurrences. Tumor recurrence was significantly associated with treatment delay of ≥ 9 weeks, with 5-year RFS of 90% for group 1 compared to only 39% for group 2 (P<.001). On multivariate analysis, RT delay of ≥ 9 weeks (P<.001), presence of lymphovascular space involvement (P=.001), and higher International Federation of Gynecology and Obstetrics grade (P=.012) were independent predictors of recurrence. In addition, RT delay of ≥ 9 weeks was an independent significant predictor for worse DSS and OS (P=.001 and P=.01, respectively). CONCLUSIONS: Delay in administering adjuvant RT after hysterectomy was associated with worse survival endpoints. Our data suggest that shorter time interval between hysterectomy and start of RT may be beneficial.

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.

Histological grade predicts for recurrence in patients with uterine endometrioid carcinoma without myometrial involvement.

AIM: To evaluate clinical outcomes and identify factors predictive for recurrence in patients with 1988 (FIGO) stage IA uterine endometrioid carcinoma. PATIENTS AND METHODS: Patients who underwent hysterectomy for stage IA carcinoma were identified in our database. Fisher's exact and χ(2) tests were used to identify factors that influenced outcome. Survival plots were generated according to Kaplan-Meier product-limit method and the log-rank test was used to determine significance. RESULTS: A total of 121 patients were identified. Eighty-seven percent (n=105) had tumor FIGO grade 1, 9% (n=11) grade 2, and 4% (n=5) grade 3 tumors. Six patients (5%) experienced recurrence. The 5-year recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) were 93%, 95%, and 85%, respectively. On univariate analysis, tumor FIGO grade 2/3 was strongly associated with tumor recurrence (p=0.003), DSS (p=0.016), and OS (p=0.023). The 5-year RFS, DSS, and OS were 65.1%, 73.9%, and 63.9% respectively for patients with grade 2 and 3 tumors, which were significantly less than the corresponding rates of 97.5% (p ≤ 0.0001), 98.6% (p=0.001), and 87.7% (p=0.024) for patients with grade 1 tumors. CONCLUSION: In this large cohort of patients, RFS, DSS and OS were excellent. Patients with FIGO grade 2/3 tumors had worse outcomes compared to those with grade 1 tumors. Therefore, while most patients with stage IA disease do not need adjuvant treatment after hysterectomy, our results suggest that patients with higher-grade tumors have an increased likelihood for recurrence and they may benefit from counseling regarding adjuvant therapies.

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.

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.

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. Student's 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.

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.