Leslie S. Bradford

Platinum resistance after neoadjuvant chemotherapy compared to primary surgery in patients with advanced epithelial ovarian carcinoma.

OBJECTIVE Primary debulking surgery (PDS) has historically been the standard treatment for advanced ovarian cancer. Recent data appear to support a paradigm shift toward neoadjuvant chemotherapy with interval debulking surgery (NACT-IDS) for a subset of women with advanced ovarian cancer. It remains unresolved whether NACT-IDS increases the risk of platinum resistance. We compared response to chemotherapy in patients that received NACT-IDS vs. PDS. METHODS From our Cancer Registry database we identified patients with stages IIIC and IV epithelial ovarian cancer who underwent treatment from January, 2005 to December, 2010. Standard univariate analyses were performed, as were multivariable analysis with logistic regression. The Kaplan-Meier method was used to generate survival data. RESULTS The study population consisted of 425 patients, 95 (22.3%) underwent NACT-IDS and 330 (77.6%) PDS. After the initial platinum-based chemotherapy, 42 (44.2%) women in the NACT-IDS group were considered to have platinum resistant disease, compared to 103 (31.2%) in the PDS group (P=0.01). When multivariate logistic regression was used to control for factors independently associated with platinum resistance, NACT-IDS was no longer associated with an initial increased risk. However, in women that had a recurrence and were retreated with platinum-based chemotherapy, 32 (88.8%) in the NACT-IDS group had developed a recurrence within six months and were considered platinum resistant, compared to 62 (55.3%) in the PDS (P<0.001). CONCLUSION In women with EOC that have a recurrence and are treated again with platinum-based chemotherapy, NACT-IDS appears to increase the risk of platinum resistance.

Cervical cancer screening and prevention in low-resource settings.

Cervical cancer is both preventable and curable, yet it remains one of the leading causes of mortality in women worldwide. Approximately 88% of cervical cancer cases are diagnosed in low-resource countries, yet very few resources are allocated to prevention and treatment programs. In fact, it is estimated that only 5% of women in low-resources countries are screened appropriately for cervical cancer. Cytology-based programs are not feasible because of lack of healthcare infrastructure and cost, thus alternative methods of cancer screening, such as visual inspection with acetic acid and HPV-DNA testing, have been intensively studied and are reviewed in this article.

Advances in the management of recurrent endometrial cancer.

Objective:Endometrial carcinoma is the most common malignancy of the female reproductive tract. Although most cases are diagnosed at an early stage, endometrial carcinoma carries a poor prognosis when it recurs after previous definitive treatment or when diagnosed at an advanced stage. The purpose of this review is to summarize the contemporary management of recurrent endometrial carcinoma. Methods:A literature review was conducted on the management of advanced, recurrent, or metastatic endometrial cancer to determine the best evidence to support the roles of surgery, radiation, and medical therapy. Results:Radiation therapy (RT) has a role in the treatment of a local or regional recurrence, especially in the patient who has not had prior RT. For selected patients who experience a loco-regional recurrence and who have been treated with RT, pelvic exenteration may be an option. Those patients with metastatic disease are not curable and should be considered for palliative chemotherapy. The data support the use of carboplatin and paclitaxel as an acceptable alternative to cisplatin-based regimens. For women who progress after first-line treatment, the options are limited. Current clinical trials are evaluating the role of angiogenesis inhibitors and molecularly targeted therapy (including the mammalian target of rapamycin inhibitors and multitargeted tyrosine kinase inhibitors) with the aim of identifying other novel agents that can be exploited for treatment of advanced disease. Conclusions:The treatment of women with advanced, recurrent, or metastatic endometrial cancer represents an unmet need in oncology. Robust clinical trials are required to explore how to improve on therapy. The incorporation of molecularly targeted agents has the potential to improve outcomes for women who require treatment in both the first-line and second-line settings.

Patient, treatment and discharge factors associated with hospital readmission within 30 days after surgical cytoreduction for epithelial ovarian carcinoma

OBJECTIVE Hospital readmissions are common, costly and increasingly viewed as adverse events. In gynecologic oncology, data on readmissions are limited. The goal of this study was to examine the patient, treatment and discharge factors associated with unplanned readmission after cytoreductive surgery. METHODS We identified all patients with stages II-IV ovarian cancer who underwent surgical cytoreduction at our institution between 2003 and 2011. A retrospective chart review was performed, and clinical variables were extracted. Utilizing linear and logistic regression, these clinical variables were correlated with risk of readmission. RESULTS A total of 460 patients were included in the analysis, with the majority having a stage IIIC high grade serous cancer. Optimal cytoreduction (<1.0 cm residual disease) was obtained in 368 patients (81%), and 233 patients (50%) underwent at least one radical procedure. Perioperative complications were observed in 148 patients (32%). A large proportion of our cohort was discharged to rehabilitation facilities (12%) or with a visiting nurse (38%). Fifty five patients (12%) were readmitted within 30 days. On multivariate logistic regression, reoperation and perioperative cardiopulmonary event were the only factors associated with readmission (OR=3.2, 95% CI=1.7-6.0). Discharge home with ancillary services was not protective against readmission, even when controlling for perioperative complications (OR=1.18, 95% CI=0.53-2.64). CONCLUSIONS Readmission after surgical cytoreduction affected 12% of our population. Multivariate analyses suggested perioperative complications, particularly reoperation and cardiopulmonary event, placed the patient at the greatest risk. Age, comorbidities, surgical radicality and discharge with visiting nurse services/rehabilitation facility did not affect the likelihood of readmission.

Racial disparities in cervical cancer survival over time

The purpose of this study is to examine changes over time in survival for African American (AA) and white women diagnosed with cervical cancer (CC).

Carcinosarcoma of the ovary compared to papillary serous ovarian carcinoma: A SEER analysis

OBJECTIVE The aims of this study are to determine if outcomes of patients with ovarian carcinosarcoma (OCS) differ from women with high grade papillary serous ovarian carcinoma when compared by stage as well as to identify any associated clinico-pathologic factors. METHODS The Surveillance, Epidemiology, and End Results (SEER) Program data for all 18 registries from 1998 to 2009 was reviewed to identify women with OCS and high grade papillary serous carcinoma of the ovary. Demographic and clinical data were compared, and the impact of tumor histology on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazard model. RESULTS The final study group consisted of 14,753 women. 1334 (9.04%) had OCS and 13,419 (90.96%) had high grade papillary serous carcinoma of the ovary. Overall, women with OCS had a worse five-year, disease specific survival rate, 28.2% vs. 38.4% (P<0.001). This difference persisted for each FIGO disease stages I-IV, with five year survival consistently worse for women with OCS compared with papillary serous carcinoma. Over the entire study period, after adjusting for histology, age, period of diagnosis, SEER registry, marital status, stage, surgery, radiotherapy, lymph node dissection, and history of secondary malignancy after the diagnosis of ovarian cancer, carcinosarcoma histology was associated with decreased cancer-specific survival. CONCLUSIONS OCS is associated with a poor prognosis compared to high grade papillary serous carcinoma of the ovary. This difference was noted across all FIGO stages.

Assessing the efficacy of targeting the phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway in endometrial cancer.

OBJECTIVE Alterations in the PI3K pathway are prevalent in endometrial cancer due to PIK3CA mutation and loss of PTEN. We investigated the anti-tumor activity of the PI3K inhibitor NVP BKM-120 (BKM) as a single agent and in combination with standard cytotoxic chemotherapy in a human primary endometrial xenograft model. METHODS NOD/SCID mice bearing xenografts of primary human tumors with and without PIK3CA gene mutations were divided into two and four arm cohorts with equivalent tumor volumes. BKM was administered alone and in combination with paclitaxel and carboplatin (P/C) and endometrial xenograft tumor volumes were assessed. Tumors from the BKM, P/C, P/C+BKM and vehicle treated mice were processed for determination of PI3K/AKT/mTOR pathway activation. RESULTS In both single agent experiments, BKM resulted in significant tumor growth suppression starting at days 5-10 compared to the linear growth observed in vehicle treated tumors (p<0.04 in all experiments). Tumor resurgence manifested between days 14 and 25 (p<0.03). When BKM was combined with P/C, this resistance pattern failed to develop in three separate xenograft lines (p<0.05). Synergistic tumor growth suppression (p<0.05) of only one xenograft tumor with no detected PIK3CA mutation was observed. Acute treatment with BKM led to a decrease in pAKT levels. CONCLUSION Independent of PIK3CA gene mutation, BKM mediated inhibition of the PI3K/AKT/mTOR pathway in endometrial tumors precludes tumor growth in a primary xenograft model. While a pattern of resistance emerges, this effect appears to be mitigated by the addition of conventional cytotoxic chemotherapy.

Laparoendoscopic single-site surgery in gynecology: a review of the literature, tools, and techniques.

Recent decades have witnessed a tremendous shift from laparotomy to laparoscopy as the surgical approach of choice in gynecology. Completion of increasingly complicated procedures has been facilitated by technical advances in instrumentation. Lately, increasing attention has been paid to reducing both the number and size of laparoscopic incisions, with the ultimate goal being the absence of any visible scar. Laparoendoscopic single-site surgery (LESS), or single-incision laparoscopy, describes the use of 1 small skin incision to complete laparoscopic surgical procedures where traditionally multiple incisions were created. In addition to examining the developing literature related to LESS in gynecology, the aims of this review were to describe the technical challenges encountered during performance of LESS and to provide practical solutions for instrumentation and surgical techniques that allow them to be overcome. Target Audience: Obstetricians and gynecologists, family physicians Learning Objectives: After completing this CME activity, physicians should be better able to identify potential benefits of LESS, and implement practical solutions for instrumentation and surgical techniques to overcome technical challenges faced during LESS.

Mucinous Adenocarcinoma of the Endometrium Compared With Endometrioid Endometrial Cancer: A SEER Analysis.

Objective:Mucinous endometrial cancer (MEC) is a rare histologic subtype of endometrial cancers. The purpose of this study is to compare the outcomes of patients with MEC with patients with endometrioid endometrial cancers (EEC), and to determine whether there are significant clinicopathologic differences between these tumors. Methods:Surveillance, Epidemiology, and End Results (SEER) Program data for 1988 to 2009 was reviewed. Demographic and clinical data were compared. The impact of histology on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. Results:The study group consisted of 104,659 women, 103,097 (98.5%) had EEC and 1562 (1.5%) MEC. The mean age at diagnosis for EEC and MEC was 62 and 63.4, respectively (P<0.001). MEC tumors were more frequently classified as grade 1 (51.3% vs. 44%; P<0.001). In patients with MEC, a higher rate of pelvic lymph node metastasis (16.3% vs. 10.4%; P<0.001) was noted, but not para-aortic lymph node metastasis (5.1% vs. 4%; P=0.1). After adjusting for race, period of diagnosis, SEER registry, marital status, stage, age, surgery, radiotherapy, grade, histology, and lymph node dissection, there was no difference in survival between MEC and EEC (hazard ratio 0.90; 95% confidence interval, 0.78-1.05). Conclusions:Mucinous histology does not significantly affect survival when compared with endometrioid histology in endometrial cancer. Patients with MEC were more likely to have positive pelvic lymph nodes at the time of surgery.

Racial disparities and changes in clinical characteristics and survival for vulvar cancer over time

OBJECTIVE The purpose of this study was to examine changes over time in survival for African-American (AA) and white women diagnosed with squamous cell carcinoma of the vulva. STUDY DESIGN The Surveillance, Epidemiology, and End Results (SEER) Program for 1973-2009 was used for this analysis. We evaluated racial differences in survival between AA and white women. Kaplan-Meier and Cox proportional hazards survival methods were used to assess differences in survival by race by decade of diagnosis. RESULTS The study sample included 5867 women, including 5379 whites (91.6%) and 488 AA (8.3%). AA women were younger (57 vs 67 years; P < .001) and had a higher rate of distant metastasis (6.1% vs 3.7%; P < .001). AA women had surgery less frequently (84.2% vs 87.6%; P = .03) and more frequently radiotherapy (24.2% vs 20.6%; P < .001). AA women had a hazard ratio (HR) of 0.84 (95% confidence interval [CI], 0.74-0.95) of all-cause mortality and 0.66 (95% CI, 0.53-0.82) of vulvar cancer mortality compared with whites. Adjusting for SEER Registry, marital status, stage, age, surgery, radiotherapy, grade, lymph node status, and decade, AA women had an HR of 0.67 (95% CI, 0.53-0.84) of vulvar cancer-related mortality compared with whites. After adjusting for the same variables, there was a significant difference in survival between AA and whites in the periods of 1990-1999 (HR, 0.62; 95% CI, 0.41-0.95) and 2000-2009 (HR, 0.46; 95% CI, 0.30-0.72) but not earlier. CONCLUSION AA presented at a significantly younger age compared with white women and had better survival compared with whites.