Georgia A. McCann

Addition of bevacizumab to weekly paclitaxel significantly improves progression-free survival in heavily pretreated recurrent epithelial ovarian cancer

OBJECTIVE Weekly paclitaxel has been shown to be an effective cytotoxic regimen for recurrent epithelial ovarian cancer (EOC), and may act through inhibition of angiogenesis. Bevacizumab, a potent angiogenesis inhibitor, has also been shown to have activity in patients with EOC. Therefore, we sought to determine if the addition of bevacizumab to weekly paclitaxel led to an increased survival compared to weekly paclitaxel alone. METHODS A single institutional review was conducted for patients with recurrent EOC treated with weekly paclitaxel (60-70mg/m(2)) on days 1, 8, 15, and 22 of a 28day cycle and those treated with weekly paclitaxel and bevacizumab (10-15mg/kg on day 1 and 15). Response rates (RR) were calculated, and progression-free survival (PFS), and overall survival (OS) were compared using Kaplan-Meier survival analysis. RESULTS Twenty-nine patients treated with weekly paclitaxel and 41 patients treated with paclitaxel/bevacizumab were identified. The groups were similar in demographics, initial optimal cytoreduction, stage, histology, grade, platinum sensitivity, and median number of previous regimens (4 vs. 4, p=0.69).The overall response rate (ORR) was 63% (complete response (CR) 34% and partial response (PR) 29%) for paclitaxel/bevacizumab and 48% (CR 17% and PR 31%) for weekly paclitaxel (p=0.23). Improvement in PFS was seen in those treated with paclitaxel/bevacizumab in comparison to weekly paclitaxel alone (median PFS 13.2 vs. 6.2months, p<.01). There was a trend towards improved OS for paclitaxel/bevacizumab (median OS 20.6 vs. 9.1months; p=0.12). Toxicities were similar between the two regimens although more bowel perforations (2 vs. 0) were seen in the paclitaxel/bevacizumab group. CONCLUSION A significant increase in PFS with a trend towards improved OS was demonstrated in this heavily pretreated population treated with paclitaxel/bevacizumab as compared to weekly paclitaxel alone. This data should be helpful in guiding future trials to determine the optimal care for women with recurrent EOC.

HO-3867, a Safe STAT3 Inhibitor, Is Selectively Cytotoxic to Ovarian Cancer

STAT3 is well corroborated preclinically as a cancer therapeutic target, but tractable translational strategies for its blockade by small molecule inhibitors have remained elusive. In this study, we report the development of a novel class of bifunctional STAT3 inhibitors, based on conjugation of a diarylidenyl-piperidone (DAP) backbone to an N-hydroxypyrroline (-NOH) group, which exhibits minimal toxicity against normal cells and good oral bioavailability. Molecular modeling studies of this class suggested direct interaction with the STAT3 DNA binding domain. In particular, the DAP compound HO-3867 selectively inhibited STAT3 phosphorylation, transcription, and DNA binding without affecting the expression of other active STATs. HO-3867 exhibited minimal toxicity toward noncancerous cells and tissues but induced apoptosis in ovarian cancer cells. Pharmacologic analysis revealed greater bioabsorption and bioavailability of the active (cytotoxic) metabolites in cancer cells compared with normal cells. The selective cytotoxicity of HO-3867 seemed to be multifaceted, eliciting differential activation of the Akt pathway in normal versus cancer cells. RNAi attenuation experiments confirmed the requirement of STAT3 for HO-3867-mediated apoptosis in ovarian cancer cells. In vivo testing showed that HO-3867 could block xenograft tumor growth without toxic side effects. Furthermore, in primary human ovarian cancer cells isolated from patient ascites, HO-3867 inhibited cell migration/invasion and survival. Our results offer preclinical proof-of-concept for HO-3867 as a selective STAT3 inhibitor to treat ovarian cancer and other solid tumors where STAT3 is widely upregulated.

Clinical predictors of bevacizumab-associated gastrointestinal perforation.

OBJECTIVES Bevacizumab is a generally well-tolerated drug, but bevacizumab-associated gastrointestinal perforations (BAP) occur in 0 to 15% of patients with ovarian carcinoma. Our goal was to evaluate the clinical predictors of BAP in order to identify factors, which may preclude patients from receiving treatment. METHODS We conducted a review of patients with recurrent epithelial ovarian carcinoma treated with bevacizumab between 2006 and 2009. Demographic and treatment data were collected for statistical analysis. RESULTS Eighty-two patients were identified; perforation occurred in 8 (9.76%). Among patients with perforation, a significantly higher incidence of prior bowel surgeries (p=0.0008) and prior bowel obstruction or ileus (p<0.0001) were found compared to non-perforated patients. The median age at onset of bevacizumab in the perforated group was 3 years younger (60 vs. 63 years, p=0.61). The incidence of thromboembolic events, GI comorbidities, number of prior chemotherapies, and body mass index were similar between the groups. None of the patients in the perforated group developed grade 3 or 4 hypertension, compared to a 32.4% incidence among the non-perforated patients (p=0.09). Upon multivariate analysis, when controlled for age greater or less than 60, prior bowel surgery, obstruction/ileus, and grade 3 or 4 hypertension, only the presence of obstruction/ileus was noted to be a significant predictor of perforation (p=0.04). CONCLUSIONS Predicting BAP remains a challenge. Bowel obstruction or ileus appears to be associated with increased risk of BAP.

HO-3867, a STAT3 inhibitor induces apoptosis by inactivation of STAT3 activity in BRCA1-mutated ovarian cancer cells

BRCA1 plays an important role in DNA damage and repair, homologous recombination, cell-cycle regulation and apoptosis. BRCA-mutated ovarian cancer often presents at an advanced stage, however, tend to have better response to platinum-based chemotherapy as compared with sporadic cases of epithelial ovarian cancer (EOC). In spite of this, most patients will develop a recurrence and eventually succumb to the disease. Preclinical studies are currently investigating natural compounds and their analogs for tumor-directed targets in ovarian cancer. The aim of this study is to investigate whether the STAT3 inhibitor HO-3867, a novel curcumin analog, has a therapeutic effect on BRCA1-mutated ovarian cancer. Our novel agent, HO-3867 and a commercial STAT3 inhibitor, STATTIC, significantly inhibited BRCA-mutated ovarian cancer cells in vitro in a dose- and time-dependent manner. BRCA-mutated ovarian cancer cells treated with HO-3867 exhibited a significant degree of apoptosis with elevated levels of cleaved caspase-3, caspase-7 and PARP. HO-3867 treatment induced more reactive oxygen species (ROS) in BRCA-mutated cells compared with wild-type cells, however, there was no increased ROS when benign ovarian surface epithelial cells were treated with HO-3867. BRCA1-mutated cancer cells had higher expression of Tyrosine-phosphorylated STAT3 (pTyr705) as compared with other STAT proteins. Furthermore, treatment of these cells with HO-3867 resulted in decreased expression of pTyr705 and its downstream targets cyclin D1, Bcl-2 and survivin. In addition, overexpression of STAT3 cDNA provided resistance to HO-3867-induced apoptosis. Our results show that HO-3867, a potent STAT3 inhibitor, may have a role as a biologically targeted agent for BRCA1-mutated cancers either as an adjunct to cytotoxic chemotherapy or as a single agent.

Lymphatic mapping and sentinel lymph node dissection compared to complete lymphadenectomy in the management of early-stage vulvar cancer: A cost-utility analysis

OBJECTIVE Sentinel lymph node biopsy (SLNB) is an acceptable method of evaluating groin lymph nodes in women with vulvar cancer. The purpose of this study is to assess the cost and effectiveness of SLNB compared to universal inguinofemoral lymphadenectomy (LND) for vulvar cancer. METHODS A modified Markov decision model was generated to compare two surgical approaches for newly diagnosed, early-stage vulvar cancer: (1) radical vulvectomy+LND and (2) radical vulvectomy+SLNB. Published data were used to estimate survival outcomes, probability of positive lymph nodes and lymphedema. Costs of surgery and radiation and lymphedema therapies were estimated from published data. Lymphedemas effect on quality of life (QOL) was extrapolated from other disease sites and assigned a utility score of 0.84. Multiple sensitivity analyses were performed. RESULTS SLNB was less costly (

Safe and targeted anticancer therapy for ovarian cancer using a novel class of curcumin analogs

13,449 versus

The impact of close surgical margins after radical hysterectomy for early-stage cervical cancer

14,261) and more effective (4.16 quality-adjusted life years (QALYs) versus 4.00 QALYs) than LND. The model was sensitive to the impact of lymphedema on QOL. Unless the impact of lymphedema on QOL was minimal (utility score>0.975) SLNB dominated LND. Variations in the rate of positive SLNB and probability of lymphedema over clinically reasonable ranges did not alter the results. CONCLUSIONS SLNB is a cost-effective strategy for the treatment of newly diagnosed vulvar cancer, mainly due to the impact of lymphedema on QOL.

Neuroendocrine carcinoma of the uterine cervix: the role of multimodality therapy in early-stage disease.

A diagnosis of advanced ovarian cancer is the beginning of a long and arduous journey for a patient. Worldwide, approximately half of the individuals undergoing therapy for advanced cancer will succumb to the disease, or consequences of treatment. Well-known and widely-used chemotherapeutic agents such as cisplatin, paclitaxel, 5-fluorouracil, and doxorubicin are toxic to both cancer and non-cancerous cells, and have debilitating side effects Therefore, development of new targeted anticancer therapies that can selectively kill cancer cells while sparing the surrounding healthy tissues is essential to develop more effective therapies. We have developed a new class of synthetic curcumin analogs, diarylidenyl-piperidones (DAPs), which have higher anticancer activity and enhanced bio-absorption than curcumin. The DAP backbone structure exhibits cytotoxic (anticancer) activity, whereas the N-hydroxypyrroline (-NOH) moiety found on some variants functions as a cellular- or tissue-specific modulator (antioxidant) of cytotoxicity. The anticancer activity of the DAPs has been evaluated using a number of ovarian cancer cell lines, and the safety has been evaluated in a number of non-cancerous cell lines. Both variations of the DAP compounds showed similar levels of cell death in ovarian cancer cells, however the compounds with the -NOH modification were less toxic to non-cancerous cells. The selective cytotoxicity of the DAP–NOH compounds suggests that they will be useful as safe and effective anticancer agents. This article reviews some of the key findings of our work with the DAP compounds, and compares this to some of the targeted therapies currently used in ovarian cancer therapy.

Hereditary cancer syndromes with high risk of endometrial and ovarian cancer: Surgical options for personalized care

OBJECTIVE While it is known that positive surgical margins increase the risk of cervical cancer recurrence, little is known about the effect of close surgical margins (CSM). Therefore, we set out to determine the impact of margin status on recurrence and survival in patients with early-stage cervical cancer. METHODS A retrospective review was conducted of patients undergoing radical hysterectomy from 2000 to 2010 with Stage IA2-IIA cervical cancer. CSM were defined as ≤5mm; association with other clinicopathologic factors as well as recurrence and survival was evaluated. RESULTS Of the 119 patients, 75 (63%) with CSM had a recurrence rate of 24% compared to 9% without CSM. Though not independently associated with recurrence, CSM were significantly associated with positive lymph nodes (44% vs. 18%), positive parametria (33.3% vs. 2.3%), larger tumors (3.5 vs. 2.5cm), greater depth of stromal invasion (DOI) (84% vs. 33%), and lymphovascular space invasion (LVSI) (61.3% vs. 34.1%). We failed to find an association between adjuvant therapy and recurrence in those with CSM. Exploratory analysis revealed that a surgical margin of ≤2mm was significantly associated with an increased risk of overall recurrence (36% vs. 9%, p=0.009) as well as loco-regional recurrence (22% vs. 4%, p=0.0034). CONCLUSIONS Surgical margins of ≤5mm on radical hysterectomy specimens are often associated with other high or intermediate risk factors for recurrence. While not a proven independent risk factor, the distance to surgical margin may warrant further investigation as an intermediate risk factor along with tumor size, DOI and LVSI.

Is bariatric surgery an option for women with gynecologic cancer? Examining weight loss counseling practices and training among gynecologic oncology providers

BACKGROUND Neuroendocrine carcinomas (NECs) of the cervix comprise only 2% of all cervical cancers. Prospective data is limited and treatment guidelines rely on retrospective reviews and literature from lung NEC. The objective of this study was to report our experience in the management of this rare disease. METHODS This was an IRB-approved retrospective review. Study criteria included patients with cervical NEC diagnosed between 1990 and 2012. Demographic, treatment and survival data was collected. Progression free survival (PFS) and overall survival (OS) were assessed. RESULTS Twenty-six patients met inclusion criteria. Advanced-stage disease (II-IV) was diagnosed in 58% (n=15) of patients. Of the eleven patients with stage I disease, five were treated with platinum-based neoadjuvant chemotherapy (NACT), six with initial radical surgery, and seven received adjuvant therapy including chemotherapy and/or radiation. Nine patients (82%) are currently without evidence of disease (NED). Patients with stage I disease had significantly improved PFS and OS compared to stages II-IV with a median OS that was not reached and 12.1 months, respectively (p=0.0013). The majority of stage I patients with lymph node metastasis and large tumors achieved durable remission with triple-modality therapy including NACT and surgery followed by adjuvant therapy. CONCLUSIONS Cervical NEC is an aggressive disease associated with a high mortality rate. Patients with advanced-stage disease have a poor prognosis regardless of therapy. However, multimodality with consideration of triple-modality therapy in early-stage disease has the potential for complete response and long-term survival, supporting the goal of curative intent in these patients.